TY - JOUR AB - The plant-signaling molecule auxin triggers fast and slow cellular responses across land plants and algae. The nuclear auxin pathway mediates gene expression and controls growth and development in land plants, but this pathway is absent from algal sister groups. Several components of rapid responses have been identified in Arabidopsis, but it is unknown if these are part of a conserved mechanism. We recently identified a fast, proteome-wide phosphorylation response to auxin. Here, we show that this response occurs across 5 land plant and algal species and converges on a core group of shared targets. We found conserved rapid physiological responses to auxin in the same species and identified rapidly accelerated fibrosarcoma (RAF)-like protein kinases as central mediators of auxin-triggered phosphorylation across species. Genetic analysis connects this kinase to both auxin-triggered protein phosphorylation and rapid cellular response, thus identifying an ancient mechanism for fast auxin responses in the green lineage. AU - Kuhn, Andre AU - Roosjen, Mark AU - Mutte, Sumanth AU - Dubey, Shiv Mani AU - Carrillo Carrasco, Vanessa Polet AU - Boeren, Sjef AU - Monzer, Aline AU - Koehorst, Jasper AU - Kohchi, Takayuki AU - Nishihama, Ryuichi AU - Fendrych, Matyas AU - Sprakel, Joris AU - Friml, Jiří AU - Weijers, Dolf ID - 14826 IS - 1 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - RAF-like protein kinases mediate a deeply conserved, rapid auxin response VL - 187 ER - TY - JOUR AB - The phytohormone auxin and its directional transport through tissues play a fundamental role in development of higher plants. This polar auxin transport predominantly relies on PIN-FORMED (PIN) auxin exporters. Hence, PIN polarization is crucial for development, but its evolution during the rise of morphological complexity in land plants remains unclear. Here, we performed a cross-species investigation by observing the trafficking and localization of endogenous and exogenous PINs in two bryophytes, Physcomitrium patens and Marchantia polymorpha, and in the flowering plant Arabidopsis thaliana. We confirmed that the GFP fusion did not compromise the auxin export function of all examined PINs by using radioactive auxin export assay and by observing the phenotypic changes in transgenic bryophytes. Endogenous PINs polarize to filamentous apices, while exogenous Arabidopsis PINs distribute symmetrically on the membrane in both bryophytes. In Arabidopsis root epidermis, bryophytic PINs show no defined polarity. Pharmacological interference revealed a strong cytoskeleton dependence of bryophytic but not Arabidopsis PIN polarization. The divergence of PIN polarization and trafficking is also observed within the bryophyte clade and between tissues of individual species. These results collectively reveal a divergence of PIN trafficking and polarity mechanisms throughout land plant evolution and a co-evolution of PIN sequence-based and cell-based polarity mechanisms. AU - Tang, Han AU - Lu, KJ AU - Zhang, Y AU - Cheng, YL AU - Tu, SL AU - Friml, Jiří ID - 14251 IS - 1 JF - Plant Communications SN - 2590-3462 TI - Divergence of trafficking and polarization mechanisms for PIN auxin transporters during land plant evolution VL - 5 ER - TY - JOUR AB - The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its closest homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study largely extend the current notions of GN function. We show that GN, but not GNL1, localizes to the cell periphery at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that the cell periphery is the major site of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations en route to the cell periphery. A study of GN-GNL1 chimeric ARF-GEFs indicates that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps toward the elucidation of the mechanism underlying unique cellular and development functions of GNOM. AU - Adamowski, Maciek AU - Matijevic, Ivana AU - Friml, Jiří ID - 15033 JF - eLife KW - General Immunology and Microbiology KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Medicine KW - General Neuroscience SN - 2050-084X TI - Developmental patterning function of GNOM ARF-GEF mediated from the cell periphery VL - 13 ER - TY - JOUR AB - Salicylic acid (SA) plays important roles in different aspects of plant development, including root growth, where auxin is also a major player by means of its asymmetric distribution. However, the mechanism underlying the effect of SA on the development of rice roots remains poorly understood. Here, we show that SA inhibits rice root growth by interfering with auxin transport associated with the OsPIN3t- and clathrin-mediated gene regulatory network (GRN). SA inhibits root growth as well as Brefeldin A-sensitive trafficking through a non-canonical SA signaling mechanism. Transcriptome analysis of rice seedlings treated with SA revealed that the OsPIN3t auxin transporter is at the center of a GRN involving the coat protein clathrin. The root growth and endocytic trafficking in both the pin3t and clathrin heavy chain mutants were SA insensitivity. SA inhibitory effect on the endocytosis of OsPIN3t was dependent on clathrin; however, the root growth and endocytic trafficking mediated by tyrphostin A23 (TyrA23) were independent of the pin3t mutant under SA treatment. These data reveal that SA affects rice root growth through the convergence of transcriptional and non-SA signaling mechanisms involving OsPIN3t-mediated auxin transport and clathrin-mediated trafficking as key components. AU - Jiang, Lihui AU - Yao, Baolin AU - Zhang, Xiaoyan AU - Wu, Lixia AU - Fu, Qijing AU - Zhao, Yiting AU - Cao, Yuxin AU - Zhu, Ruomeng AU - Lu, Xinqi AU - Huang, Wuying AU - Zhao, Jianping AU - Li, Kuixiu AU - Zhao, Shuanglu AU - Han, Li AU - Zhou, Xuan AU - Luo, Chongyu AU - Zhu, Haiyan AU - Yang, Jing AU - Huang, Huichuan AU - Zhu, Zhengge AU - He, Xiahong AU - Friml, Jiří AU - Zhang, Zhongkai AU - Liu, Changning AU - Du, Yunlong ID - 12878 IS - 1 JF - Plant Journal SN - 0960-7412 TI - Salicylic acid inhibits rice endocytic protein trafficking mediated by OsPIN3t and clathrin to affect root growth VL - 115 ER - TY - JOUR AB - The primary cell wall is a fundamental plant constituent that is flexible but sufficiently rigid to support the plant cell shape. Although many studies have demonstrated that reactive oxygen species (ROS) serve as important signaling messengers to modify the cell wall structure and affect cellular growth, the regulatory mechanism underlying the spatial-temporal regulation of ROS activity for cell wall maintenance remains largely unclear. Here, we demonstrate the role of the Arabidopsis (Arabidopsis thaliana) multicopper oxidase-like protein skewed 5 (SKU5) and its homolog SKU5-similar 1 (SKS1) in root cell wall formation through modulating ROS homeostasis. Loss of SKU5 and SKS1 function resulted in aberrant division planes, protruding cell walls, ectopic deposition of iron, and reduced nicotinamide adeninedinucleotide phosphate (NADPH) oxidase-dependent ROS overproduction in the root epidermis–cortex and cortex–endodermis junctions. A decrease in ROS level or inhibition of NADPH oxidase activity rescued the cell wall defects of sku5 sks1 double mutants. SKU5 and SKS1 proteins were activated by iron treatment, and iron over-accumulated in the walls between the root epidermis and cortex cell layers of sku5 sks1. The glycosylphosphatidylinositol-anchored motif was crucial for membrane association and functionality of SKU5 and SKS1. Overall, our results identified SKU5 and SKS1 as regulators of ROS at the cell surface for regulation of cell wall structure and root cell growth. AU - Chen, C AU - Zhang, Y AU - Cai, J AU - Qiu, Y AU - Li, L AU - Gao, C AU - Gao, Y AU - Ke, M AU - Wu, S AU - Wei, C AU - Chen, J AU - Xu, T AU - Friml, Jiří AU - Wang, J AU - Li, R AU - Chao, D AU - Zhang, B AU - Chen, X AU - Gao, Z ID - 13213 IS - 3 JF - Plant Physiology SN - 0032-0889 TI - Multi-copper oxidases SKU5 and SKS1 coordinate cell wall formation using apoplastic redox-based reactions in roots VL - 192 ER - TY - JOUR AB - Treating sick group members is a hallmark of collective disease defence in vertebrates and invertebrates alike. Despite substantial effects on pathogen fitness and epidemiology, it is still largely unknown how pathogens react to the selection pressure imposed by care intervention. Using social insects and pathogenic fungi, we here performed a serial passage experiment in the presence or absence of colony members, which provide social immunity by grooming off infectious spores from exposed individuals. We found specific effects on pathogen diversity, virulence and transmission. Under selection of social immunity, pathogens invested into higher spore production, but spores were less virulent. Notably, they also elicited a lower grooming response in colony members, compared with spores from the individual host selection lines. Chemical spore analysis suggested that the spores from social selection lines escaped the caregivers’ detection by containing lower levels of ergosterol, a key fungal membrane component. Experimental application of chemically pure ergosterol indeed induced sanitary grooming, supporting its role as a microbe-associated cue triggering host social immunity against fungal pathogens. By reducing this detection cue, pathogens were able to evade the otherwise very effective collective disease defences of their social hosts. AU - Stock, Miriam AU - Milutinovic, Barbara AU - Hönigsberger, Michaela AU - Grasse, Anna V AU - Wiesenhofer, Florian AU - Kampleitner, Niklas AU - Narasimhan, Madhumitha AU - Schmitt, Thomas AU - Cremer, Sylvia ID - 12543 JF - Nature Ecology and Evolution TI - Pathogen evasion of social immunity VL - 7 ER - TY - JOUR AB - To respond to auxin, the chief orchestrator of their multicellularity, plants evolved multiple receptor systems and signal transduction cascades. Despite decades of research, however, we are still lacking a satisfactory synthesis of various auxin signaling mechanisms. The chief discrepancy and historical controversy of the field is that of rapid and slow auxin effects on plant physiology and development. How is it possible that ions begin to trickle across the plasma membrane as soon as auxin enters the cell, even though the best-characterized transcriptional auxin pathway can take effect only after tens of minutes? Recently, unexpected progress has been made in understanding this and other unknowns of auxin signaling. We provide a perspective on these exciting developments and concepts whose general applicability might have ramifications beyond auxin signaling. AU - Fiedler, Lukas AU - Friml, Jiří ID - 14313 IS - 10 JF - Current Opinion in Plant Biology SN - 1369-5266 TI - Rapid auxin signaling: Unknowns old and new VL - 75 ER - TY - GEN AB - Clathrin-mediated endocytosis (CME) is vital for the regulation of plant growth and development by controlling plasma membrane protein composition and cargo uptake. CME relies on the precise recruitment of regulators for vesicle maturation and release. Homologues of components of mammalian vesicle scission are strong candidates to be part of the scissin machinery in plants, but the precise roles of these proteins in this process is not fully understood. Here, we characterised the roles of Plant Dynamin-Related Proteins 2 (DRP2s) and SH3-domain containing protein 2 (SH3P2), the plant homologue to Dynamins’ recruiters, like Endophilin and Amphiphysin, in the CME by combining high-resolution imaging of endocytic events in vivo and characterisation of the purified proteins in vitro. Although DRP2s and SH3P2 arrive similarly late during CME and physically interact, genetic analysis of the Dsh3p1,2,3 triple-mutant and complementation assays with non-SH3P2-interacting DRP2 variants suggests that SH3P2 does not directly recruit DRP2s to the site of endocytosis. These observations imply that despite the presence of many well-conserved endocytic components, plants have acquired a distinct mechanism for CME. One Sentence Summary In contrast to predictions based on mammalian systems, plant Dynamin-related proteins 2 are recruited to the site of Clathrin-mediated endocytosis independently of BAR-SH3 proteins. AU - Gnyliukh, Nataliia AU - Johnson, Alexander J AU - Nagel, Marie-Kristin AU - Monzer, Aline AU - Hlavata, Annamaria AU - Isono, Erika AU - Loose, Martin AU - Friml, Jiří ID - 14591 T2 - bioRxiv TI - Role of dynamin-related proteins 2 and SH3P2 in clathrin-mediated endocytosis in plants ER - TY - JOUR AB - Lateral roots are typically maintained at non-vertical angles with respect to gravity. These gravitropic setpoint angles are intriguing because their maintenance requires that roots are able to effect growth response both with and against the gravity vector, a phenomenon previously attributed to gravitropism acting against an antigravitropic offset mechanism. Here we show how the components mediating gravitropism in the vertical primary root—PINs and phosphatases acting upon them—are reconfigured in their regulation such that lateral root growth at a range of angles can be maintained. We show that the ability of Arabidopsis lateral roots to bend both downward and upward requires the generation of auxin asymmetries and is driven by angle-dependent variation in downward gravitropic auxin flux acting against angle-independent upward, antigravitropic flux. Further, we demonstrate a symmetry in auxin distribution in lateral roots at gravitropic setpoint angle that can be traced back to a net, balanced polarization of PIN3 and PIN7 auxin transporters in the columella. These auxin fluxes are shifted by altering PIN protein phosphoregulation in the columella, either by introducing PIN3 phosphovariant versions or via manipulation of levels of the phosphatase subunit PP2A/RCN1. Finally, we show that auxin, in addition to driving lateral root directional growth, acts within the lateral root columella to induce more vertical growth by increasing RCN1 levels, causing a downward shift in PIN3 localization, thereby diminishing the magnitude of the upward, antigravitropic auxin flux. AU - Roychoudhry, S AU - Sageman-Furnas, K AU - Wolverton, C AU - Grones, Peter AU - Tan, Shutang AU - Molnar, Gergely AU - De Angelis, M AU - Goodman, HL AU - Capstaff, N AU - JPB, Lloyd AU - Mullen, J AU - Hangarter, R AU - Friml, Jiří AU - Kepinski, S ID - 14339 JF - Nature Plants SN - 2055-0278 TI - Antigravitropic PIN polarization maintains non-vertical growth in lateral roots VL - 9 ER - TY - JOUR AB - Auxin belongs among major phytohormones and governs multiple aspects of plant growth and development. The establishment of auxin concentration gradients, determines, among other processes, plant organ positioning and growth responses to environmental stimuli. Herein we report the synthesis of new NBD- or DNS-labelled IAA derivatives and the elucidation of their biological activity, fluorescence properties and subcellular accumulation patterns in planta. These novel compounds did not show auxin-like activity, but instead antagonized physiological auxin effects. The DNS-labelled derivatives FL5 and FL6 showed strong anti-auxin activity in roots and hypocotyls, which also occurred at the level of gene transcription as confirmed by quantitative PCR analysis. The auxin antagonism of our derivatives was further demonstrated in vitro using an SPR-based binding assay. The NBD-labelled compound FL4 with the best fluorescence properties proved to be unsuitable to study auxin accumulation patterns in planta. On the other hand, the strongest anti-auxin activity possessing compounds FL5 and FL6 could be useful to study binding mechanisms to auxin receptors and for manipulations of auxin-regulated processes. AU - Bieleszová, Kristýna AU - Hladík, Pavel AU - Kubala, Martin AU - Napier, Richard AU - Brunoni, Federica AU - Gelová, Zuzana AU - Fiedler, Lukas AU - Kulich, Ivan AU - Strnad, Miroslav AU - Doležal, Karel AU - Novák, Ondřej AU - Friml, Jiří AU - Žukauskaitė, Asta ID - 14447 JF - Plant Growth Regulation SN - 0167-6903 TI - New fluorescent auxin derivatives: anti-auxin activity and accumulation patterns in Arabidopsis thaliana ER - TY - JOUR AB - Amid the delays due to the global pandemic, in early October 2022, the auxin community gathered in the idyllic peninsula of Cavtat, Croatia. More than 170 scientists from across the world converged to discuss the latest advancements in fundamental and applied research in the field. The topics, from signalling and transport to plant architecture and response to the environment, show how auxin research must bridge from the molecular realm to macroscopic developmental responses. This is mirrored in this collection of reviews, contributed by participants of the Auxin 2022 meeting. AU - Del Bianco, Marta AU - Friml, Jiří AU - Strader, Lucia AU - Kepinski, Stefan ID - 14709 IS - 22 JF - Journal of Experimental Botany SN - 0022-0957 TI - Auxin research: Creating tools for a greener future VL - 74 ER - TY - JOUR AB - Soluble chaperones residing in the endoplasmic reticulum (ER) play vitally important roles in folding and quality control of newly synthesized proteins that transiently pass through the ER en route to their final destinations. These soluble residents of the ER are themselves endowed with an ER retrieval signal that enables the cell to bring the escaped residents back from the Golgi. Here, by using purified proteins, we showed that Nicotiana tabacum phytaspase, a plant aspartate-specific protease, introduces two breaks at the C-terminus of the N. tabacum ER resident calreticulin-3. These cleavages resulted in removal of either a dipeptide or a hexapeptide from the C-terminus of calreticulin-3 encompassing part or all of the ER retrieval signal. Consistently, expression of the calreticulin-3 derivative mimicking the phytaspase cleavage product in Nicotiana benthamiana cells demonstrated loss of the ER accumulation of the protein. Notably, upon its escape from the ER, calreticulin-3 was further processed by an unknown protease(s) to generate the free N-terminal (N) domain of calreticulin-3, which was ultimately secreted into the apoplast. Our study thus identified a specific proteolytic enzyme capable of precise detachment of the ER retrieval signal from a plant ER resident protein, with implications for the further fate of the escaped resident. AU - Teplova, Anastasiia AU - Pigidanov, Artemii A. AU - Serebryakova, Marina V. AU - Golyshev, Sergei A. AU - Galiullina, Raisa A. AU - Chichkova, Nina V. AU - Vartapetian, Andrey B. ID - 14776 IS - 22 JF - International Journal of Molecular Sciences KW - Inorganic Chemistry KW - Organic Chemistry KW - Physical and Theoretical Chemistry KW - Computer Science Applications KW - Spectroscopy KW - Molecular Biology KW - General Medicine KW - Catalysis SN - 1422-0067 TI - Phytaspase Is capable of detaching the endoplasmic reticulum retrieval signal from tobacco calreticulin-3 VL - 24 ER - TY - JOUR AB - Auxin is the major plant hormone regulating growth and development (Friml, 2022). Forward genetic approaches in the model plant Arabidopsis thaliana have identified major components of auxin signalling and established the canonical mechanism mediating transcriptional and thus developmental reprogramming. In this textbook view, TRANSPORT INHIBITOR RESPONSE 1 (TIR1)/AUXIN-SIGNALING F-BOX (AFBs) are auxin receptors, which act as F-box subunits determining the substrate specificity of the Skp1-Cullin1-F box protein (SCF) type E3 ubiquitin ligase complex. Auxin acts as a “molecular glue” increasing the affinity between TIR1/AFBs and the Aux/IAA repressors. Subsequently, Aux/IAAs are ubiquitinated and degraded, thus releasing auxin transcription factors from their repression making them free to mediate transcription of auxin response genes (Yu et al., 2022). Nonetheless, accumulating evidence suggests existence of rapid, non-transcriptional responses downstream of TIR1/AFBs such as auxin-induced cytosolic calcium (Ca2+) transients, plasma membrane depolarization and apoplast alkalinisation, all converging on the process of root growth inhibition and root gravitropism (Li et al., 2022). Particularly, these rapid responses are mostly contributed by predominantly cytosolic AFB1, while the long-term growth responses are mediated by mainly nuclear TIR1 and AFB2-AFB5 (Li et al., 2021; Prigge et al., 2020; Serre et al., 2021). How AFB1 conducts auxin-triggered rapid responses and how it is different from TIR1 and AFB2-AFB5 remains elusive. Here, we compare the roles of TIR1 and AFB1 in transcriptional and rapid responses by modulating their subcellular localization in Arabidopsis and by testing their ability to mediate transcriptional responses when part of the minimal auxin circuit reconstituted in yeast. AU - Chen, Huihuang AU - Li, Lanxin AU - Zou, Minxia AU - Qi, Linlin AU - Friml, Jiří ID - 13212 IS - 7 JF - Molecular Plant SN - 1752-9867 TI - Distinct functions of TIR1 and AFB1 receptors in auxin signalling. VL - 16 ER - TY - JOUR AB - The 3′,5′-cyclic adenosine monophosphate (cAMP) is a versatile second messenger in many mammalian signaling pathways. However, its role in plants remains not well-recognized. Recent discovery of adenylate cyclase (AC) activity for transport inhibitor response 1/auxin-signaling F-box proteins (TIR1/AFB) auxin receptors and the demonstration of its importance for canonical auxin signaling put plant cAMP research back into spotlight. This insight briefly summarizes the well-established cAMP signaling pathways in mammalian cells and describes the turbulent and controversial history of plant cAMP research highlighting the major progress and the unresolved points. We also briefly review the current paradigm of auxin signaling to provide a background for the discussion on the AC activity of TIR1/AFB auxin receptors and its potential role in transcriptional auxin signaling as well as impact of these discoveries on plant cAMP research in general. AU - Qi, Linlin AU - Friml, Jiří ID - 13266 IS - 2 JF - New Phytologist SN - 0028-646X TI - Tale of cAMP as a second messenger in auxin signaling and beyond VL - 240 ER - TY - JOUR AB - The phytohormone auxin plays central roles in many growth and developmental processes in plants. Development of chemical tools targeting the auxin pathway is useful for both plant biology and agriculture. Here we reveal that naproxen, a synthetic compound with anti-inflammatory activity in humans, acts as an auxin transport inhibitor targeting PIN-FORMED (PIN) transporters in plants. Physiological experiments indicate that exogenous naproxen treatment affects pleiotropic auxin-regulated developmental processes. Additional cellular and biochemical evidence indicates that naproxen suppresses auxin transport, specifically PIN-mediated auxin efflux. Moreover, biochemical and structural analyses confirm that naproxen binds directly to PIN1 protein via the same binding cavity as the indole-3-acetic acid substrate. Thus, by combining cellular, biochemical, and structural approaches, this study clearly establishes that naproxen is a PIN inhibitor and elucidates the underlying mechanisms. Further use of this compound may advance our understanding of the molecular mechanisms of PIN-mediated auxin transport and expand our toolkit in auxin biology and agriculture. AU - Xia, Jing AU - Kong, Mengjuan AU - Yang, Zhisen AU - Sun, Lianghanxiao AU - Peng, Yakun AU - Mao, Yanbo AU - Wei, Hong AU - Ying, Wei AU - Gao, Yongxiao AU - Friml, Jiří AU - Weng, Jianping AU - Liu, Xin AU - Sun, Linfeng AU - Tan, Shutang ID - 13209 IS - 6 JF - Plant Communications TI - Chemical inhibition of Arabidopsis PIN-FORMED auxin transporters by the anti-inflammatory drug naproxen VL - 4 ER - TY - JOUR AB - As a crucial nitrogen source, nitrate (NO3−) is a key nutrient for plants. Accordingly, root systems adapt to maximize NO3− availability, a developmental regulation also involving the phytohormone auxin. Nonetheless, the molecular mechanisms underlying this regulation remain poorly understood. Here, we identify low-nitrate-resistant mutant (lonr) in Arabidopsis (Arabidopsis thaliana), whose root growth fails to adapt to low-NO3− conditions. lonr2 is defective in the high-affinity NO3− transporter NRT2.1. lonr2 (nrt2.1) mutants exhibit defects in polar auxin transport, and their low-NO3−-induced root phenotype depends on the PIN7 auxin exporter activity. NRT2.1 directly associates with PIN7 and antagonizes PIN7-mediated auxin efflux depending on NO3− levels. These results reveal a mechanism by which NRT2.1 in response to NO3− limitation directly regulates auxin transport activity and, thus, root growth. This adaptive mechanism contributes to the root developmental plasticity to help plants cope with changes in NO3− availability. AU - Wang, Yalu AU - Yuan, Zhi AU - Wang, Jinyi AU - Xiao, Huixin AU - Wan, Lu AU - Li, Lanxin AU - Guo, Yan AU - Gong, Zhizhong AU - Friml, Jiří AU - Zhang, Jing ID - 13201 IS - 25 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 0027-8424 TI - The nitrate transporter NRT2.1 directly antagonizes PIN7-mediated auxin transport for root growth adaptation VL - 120 ER - TY - THES AU - Gnyliukh, Nataliia ID - 14510 KW - Clathrin-Mediated Endocytosis KW - vesicle scission KW - Dynamin-Related Protein 2 KW - SH3P2 KW - TPLATE complex KW - Total internal reflection fluorescence microscopy KW - Arabidopsis thaliana SN - 2663-337X TI - Mechanism of clathrin-coated vesicle formation during endocytosis in plants ER - TY - JOUR AB - Auxin has always been at the forefront of research in plant physiology and development. Since the earliest contemplations by Julius von Sachs and Charles Darwin, more than a century-long struggle has been waged to understand its function. This largely reflects the failures, successes, and inevitable progress in the entire field of plant signaling and development. Here I present 14 stations on our long and sometimes mystical journey to understand auxin. These highlights were selected to give a flavor of the field and to show the scope and limits of our current knowledge. A special focus is put on features that make auxin unique among phytohormones, such as its dynamic, directional transport network, which integrates external and internal signals, including self-organizing feedback. Accented are persistent mysteries and controversies. The unexpected discoveries related to rapid auxin responses and growth regulation recently disturbed our contentment regarding understanding of the auxin signaling mechanism. These new revelations, along with advances in technology, usher us into a new, exciting era in auxin research. AU - Friml, Jiří ID - 10016 IS - 5 JF - Cold Spring Harbor Perspectives in Biology SN - 1943-0264 TI - Fourteen stations of auxin VL - 14 ER - TY - JOUR AB - The synthetic strigolactone (SL) analog, rac-GR24, has been instrumental in studying the role of SLs as well as karrikins because it activates the receptors DWARF14 (D14) and KARRIKIN INSENSITIVE 2 (KAI2) of their signaling pathways, respectively. Treatment with rac-GR24 modifies the root architecture at different levels, such as decreasing the lateral root density (LRD), while promoting root hair elongation or flavonol accumulation. Previously, we have shown that the flavonol biosynthesis is transcriptionally activated in the root by rac-GR24 treatment, but, thus far, the molecular players involved in that response have remained unknown. To get an in-depth insight into the changes that occur after the compound is perceived by the roots, we compared the root transcriptomes of the wild type and the more axillary growth2 (max2) mutant, affected in both SL and karrikin signaling pathways, with and without rac-GR24 treatment. Quantitative reverse transcription (qRT)-PCR, reporter line analysis and mutant phenotyping indicated that the flavonol response and the root hair elongation are controlled by the ELONGATED HYPOCOTYL 5 (HY5) and MYB12 transcription factors, but HY5, in contrast to MYB12, affects the LRD as well. Furthermore, we identified the transcription factors TARGET OF MONOPTEROS 5 (TMO5) and TMO5 LIKE1 as negative and the Mediator complex as positive regulators of the rac-GR24 effect on LRD. Altogether, hereby, we get closer toward understanding the molecular mechanisms that underlay the rac-GR24 responses in the root. AU - Struk, Sylwia AU - Braem, Lukas AU - Matthys, Cedrick AU - Walton, Alan AU - Vangheluwe, Nick AU - Van Praet, Stan AU - Jiang, Lingxiang AU - Baster, Pawel AU - De Cuyper, Carolien AU - Boyer, Francois-Didier AU - Stes, Elisabeth AU - Beeckman, Tom AU - Friml, Jiří AU - Gevaert, Kris AU - Goormachtig, Sofie ID - 10583 IS - 1 JF - Plant & Cell Physiology KW - flavonols KW - MAX2 KW - rac-Gr24 KW - RNA-seq KW - root development KW - transcriptional regulation SN - 0032-0781 TI - Transcriptional analysis in the Arabidopsis roots reveals new regulators that link rac-GR24 treatment with changes in flavonol accumulation, root hair elongation and lateral root density VL - 63 ER - TY - JOUR AB - Much of what we know about the role of auxin in plant development derives from exogenous manipulations of auxin distribution and signaling, using inhibitors, auxins and auxin analogs. In this context, synthetic auxin analogs, such as 1-Naphtalene Acetic Acid (1-NAA), are often favored over the endogenous auxin indole-3-acetic acid (IAA), in part due to their higher stability. While such auxin analogs have proven to be instrumental to reveal the various faces of auxin, they display in some cases distinct bioactivities compared to IAA. Here, we focused on the effect of auxin analogs on the accumulation of PIN proteins in Brefeldin A-sensitive endosomal aggregations (BFA bodies), and the correlation with the ability to elicit Ca 2+ responses. For a set of commonly used auxin analogs, we evaluated if auxin-analog induced Ca 2+ signaling inhibits PIN accumulation. Not all auxin analogs elicited a Ca 2+ response, and their differential ability to elicit Ca 2+ responses correlated partially with their ability to inhibit BFA-body formation. However, in tir1/afb and cngc14, 1-NAA-induced Ca 2+ signaling was strongly impaired, yet 1-NAA still could inhibit PIN accumulation in BFA bodies. This demonstrates that TIR1/AFB-CNGC14-dependent Ca 2+ signaling does not inhibit BFA body formation in Arabidopsis roots. AU - Wang, R AU - Himschoot, E AU - Grenzi, M AU - Chen, J AU - Safi, A AU - Krebs, M AU - Schumacher, K AU - Nowack, MK AU - Moeder, W AU - Yoshioka, K AU - Van Damme, D AU - De Smet, I AU - Geelen, D AU - Beeckman, T AU - Friml, Jiří AU - Costa, A AU - Vanneste, S ID - 10717 IS - 8 JF - Journal of Experimental Botany SN - 0022-0957 TI - Auxin analog-induced Ca2+ signaling is independent of inhibition of endosomal aggregation in Arabidopsis roots VL - 73 ER - TY - JOUR AB - Auxin, one of the first identified and most widely studied phytohormones, has been and will remain a hot topic in plant biology. After more than a century of passionate exploration, the mysteries of its synthesis, transport, signaling, and metabolism have largely been unlocked. Due to the rapid development of new technologies, new methods, and new genetic materials, the study of auxin has entered the fast lane over the past 30 years. Here, we highlight advances in understanding auxin signaling, including auxin perception, rapid auxin responses, TRANSPORT INHIBITOR RESPONSE 1 and AUXIN SIGNALING F-boxes (TIR1/AFBs)-mediated transcriptional and non-transcriptional branches, and the epigenetic regulation of auxin signaling. We also focus on feedback inhibition mechanisms that prevent the over-amplification of auxin signals. In addition, we cover the TRANSMEMBRANE KINASEs (TMKs)-mediated non-canonical signaling, which converges with TIR1/AFBs-mediated transcriptional regulation to coordinate plant growth and development. The identification of additional auxin signaling components and their regulation will continue to open new avenues of research in this field, leading to an increasingly deeper, more comprehensive understanding of how auxin signals are interpreted at the cellular level to regulate plant growth and development. AU - Yu, Z AU - Zhang, F AU - Friml, Jiří AU - Ding, Z ID - 10719 IS - 2 JF - Journal of Integrative Plant Biology SN - 1672-9072 TI - Auxin signaling: Research advances over the past 30 years VL - 64 ER - TY - JOUR AB - Among the most fascinated properties of the plant hormone auxin is its ability to promote formation of its own directional transport routes. These gradually narrowing auxin channels form from the auxin source toward the sink and involve coordinated, collective polarization of individual cells. Once established, the channels provide positional information, along which new vascular strands form, for example, during organogenesis, regeneration, or leave venation. The main prerequisite of this still mysterious auxin canalization mechanism is a feedback between auxin signaling and its directional transport. This is manifested by auxin-induced re-arrangements of polar, subcellular localization of PIN-FORMED (PIN) auxin exporters. Immanent open questions relate to how position of auxin source and sink as well as tissue context are sensed and translated into tissue polarization and how cells communicate to polarize coordinately. Recently, identification of the first molecular players opens new avenues into molecular studies of this intriguing example of self-organizing plant development. AU - Hajny, Jakub AU - Tan, Shutang AU - Friml, Jiří ID - 10768 IS - 2 JF - Current Opinion in Plant Biology SN - 1369-5266 TI - Auxin canalization: From speculative models toward molecular players VL - 65 ER - TY - JOUR AB - In eukaryotes, clathrin-coated vesicles (CCVs) facilitate the internalization of material from the cell surface as well as the movement of cargo in post-Golgi trafficking pathways. This diversity of functions is partially provided by multiple monomeric and multimeric clathrin adaptor complexes that provide compartment and cargo selectivity. The adaptor-protein assembly polypeptide-1 (AP-1) complex operates as part of the secretory pathway at the trans-Golgi network (TGN), while the AP-2 complex and the TPLATE complex jointly operate at the plasma membrane to execute clathrin-mediated endocytosis. Key to our further understanding of clathrin-mediated trafficking in plants will be the comprehensive identification and characterization of the network of evolutionarily conserved and plant-specific core and accessory machinery involved in the formation and targeting of CCVs. To facilitate these studies, we have analyzed the proteome of enriched TGN/early endosome-derived and endocytic CCVs isolated from dividing and expanding suspension-cultured Arabidopsis (Arabidopsis thaliana) cells. Tandem mass spectrometry analysis results were validated by differential chemical labeling experiments to identify proteins co-enriching with CCVs. Proteins enriched in CCVs included previously characterized CCV components and cargos such as the vacuolar sorting receptors in addition to conserved and plant-specific components whose function in clathrin-mediated trafficking has not been previously defined. Notably, in addition to AP-1 and AP-2, all subunits of the AP-4 complex, but not AP-3 or AP-5, were found to be in high abundance in the CCV proteome. The association of AP-4 with suspension-cultured Arabidopsis CCVs is further supported via additional biochemical data. AU - Dahhan, DA AU - Reynolds, GD AU - Cárdenas, JJ AU - Eeckhout, D AU - Johnson, Alexander J AU - Yperman, K AU - Kaufmann, Walter AU - Vang, N AU - Yan, X AU - Hwang, I AU - Heese, A AU - De Jaeger, G AU - Friml, Jiří AU - Van Damme, D AU - Pan, J AU - Bednarek, SY ID - 10841 IS - 6 JF - Plant Cell SN - 1040-4651 TI - Proteomic characterization of isolated Arabidopsis clathrin-coated vesicles reveals evolutionarily conserved and plant-specific components VL - 34 ER - TY - JOUR AB - Despite the growing interest in using chemical genetics in plant research, small molecule target identification remains a major challenge. The cellular thermal shift assay coupled with high-resolution mass spectrometry (CETSA MS) that monitors changes in the thermal stability of proteins caused by their interactions with small molecules, other proteins, or posttranslational modifications, allows the discovery of drug targets or the study of protein–metabolite and protein–protein interactions mainly in mammalian cells. To showcase the applicability of this method in plants, we applied CETSA MS to intact Arabidopsis thaliana cells and identified the thermal proteome of the plant-specific glycogen synthase kinase 3 (GSK3) inhibitor, bikinin. A comparison between the thermal and the phosphoproteomes of bikinin revealed the auxin efflux carrier PIN-FORMED1 (PIN1) as a substrate of the Arabidopsis GSK3s that negatively regulate the brassinosteroid signaling. We established that PIN1 phosphorylation by the GSK3s is essential for maintaining its intracellular polarity that is required for auxin-mediated regulation of vascular patterning in the leaf, thus revealing cross-talk between brassinosteroid and auxin signaling. AU - Lu, Qing AU - Zhang, Yonghong AU - Hellner, Joakim AU - Giannini, Caterina AU - Xu, Xiangyu AU - Pauwels, Jarne AU - Ma, Qian AU - Dejonghe, Wim AU - Han, Huibin AU - Van De Cotte, Brigitte AU - Impens, Francis AU - Gevaert, Kris AU - De Smet, Ive AU - Friml, Jiří AU - Molina, Daniel Martinez AU - Russinova, Eugenia ID - 10888 IS - 11 JF - Proceedings of the National Academy of Sciences of the United States of America TI - Proteome-wide cellular thermal shift assay reveals unexpected cross-talk between brassinosteroid and auxin signaling VL - 119 ER - TY - JOUR AB - Calcium-dependent protein kinases (CPK) are key components of a wide array of signaling pathways, translating stress and nutrient signaling into the modulation of cellular processes such as ion transport and transcription. However, not much is known about CPKs in endomembrane trafficking. Here, we screened for CPKs that impact on root growth and gravitropism, by overexpressing constitutively active forms of CPKs under the control of an inducible promoter in Arabidopsis thaliana. We found that inducible overexpression of an constitutive active CPK30 (CA-CPK30) resulted in a loss of root gravitropism and ectopic auxin accumulation in the root tip. Immunolocalization revealed that CA-CPK30 roots have reduced PIN protein levels, PIN1 polarity defects and impaired Brefeldin A (BFA)-sensitive trafficking. Moreover, FM4-64 uptake was reduced, indicative of a defect in endocytosis. The effects on BFA-sensitive trafficking were not specific to PINs, as BFA could not induce aggregation of ARF1- and CHC-labeled endosomes in CA-CPK30. Interestingly, the interference with BFA-body formation, could be reverted by increasing the extracellular pH, indicating a pH-dependence of this CA-CPK30 effect. Altogether, our data reveal an important role for CPK30 in root growth regulation and endomembrane trafficking in Arabidopsis thaliana. AU - Wang, Ren AU - Himschoot, Ellie AU - Chen, Jian AU - Boudsocq, Marie AU - Geelen, Danny AU - Friml, Jiří AU - Beeckman, Tom AU - Vanneste, Steffen ID - 11589 JF - Frontiers in Plant Science TI - Constitutive active CPK30 interferes with root growth and endomembrane trafficking in Arabidopsis thaliana VL - 13 ER - TY - JOUR AB - Plant cell growth responds rapidly to various stimuli, adapting architecture to environmental changes. Two major endogenous signals regulating growth are the phytohormone auxin and the secreted peptides rapid alkalinization factors (RALFs). Both trigger very rapid cellular responses and also exert long-term effects [Du et al., Annu. Rev. Plant Biol. 71, 379–402 (2020); Blackburn et al., Plant Physiol. 182, 1657–1666 (2020)]. However, the way, in which these distinct signaling pathways converge to regulate growth, remains unknown. Here, using vertical confocal microscopy combined with a microfluidic chip, we addressed the mechanism of RALF action on growth. We observed correlation between RALF1-induced rapid Arabidopsis thaliana root growth inhibition and apoplast alkalinization during the initial phase of the response, and revealed that RALF1 reversibly inhibits primary root growth through apoplast alkalinization faster than within 1 min. This rapid apoplast alkalinization was the result of RALF1-induced net H+ influx and was mediated by the receptor FERONIA (FER). Furthermore, we investigated the cross-talk between RALF1 and the auxin signaling pathways during root growth regulation. The results showed that RALF-FER signaling triggered auxin signaling with a delay of approximately 1 h by up-regulating auxin biosynthesis, thus contributing to sustained RALF1-induced growth inhibition. This biphasic RALF1 action on growth allows plants to respond rapidly to environmental stimuli and also reprogram growth and development in the long term. AU - Li, Lanxin AU - Chen, Huihuang AU - Alotaibi, Saqer S. AU - Pěnčík, Aleš AU - Adamowski, Maciek AU - Novák, Ondřej AU - Friml, Jiří ID - 11723 IS - 31 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - RALF1 peptide triggers biphasic root growth inhibition upstream of auxin biosynthesis VL - 119 ER - TY - JOUR AB - Strigolactones (SLs) are a class of phytohormones that regulate plant shoot branching and adventitious root development. However, little is known regarding the role of SLs in controlling the behavior of the smallest unit of the organism, the single cell. Here, taking advantage of a classic single-cell model offered by the cotton (Gossypium hirsutum) fiber cell, we show that SLs, whose biosynthesis is fine-tuned by gibberellins (GAs), positively regulate cell elongation and cell wall thickness by promoting the biosynthesis of very-long-chain fatty acids (VLCFAs) and cellulose, respectively. Furthermore, we identified two layers of transcription factors (TFs) involved in the hierarchical regulation of this GA-SL crosstalk. The top-layer TF GROWTH-REGULATING FACTOR 4 (GhGRF4) directly activates expression of the SL biosynthetic gene DWARF27 (D27) to increase SL accumulation in fiber cells and GAs induce GhGRF4 expression. SLs induce the expression of four second-layer TF genes (GhNAC100-2, GhBLH51, GhGT2, and GhB9SHZ1), which transmit SL signals downstream to two ketoacyl-CoA synthase genes (KCS) and three cellulose synthase (CesA) genes by directly activating their transcription. Finally, the KCS and CesA enzymes catalyze the biosynthesis of very long chain fatty acids and cellulose, respectively, to regulate development of high-grade cotton fibers. In addition to providing a theoretical basis for cotton fiber improvement, our results shed light on SL signaling in plant development at the single-cell level. AU - Tian, Z AU - Zhang, Yuzhou AU - Zhu, L AU - Jiang, B AU - Wang, H AU - Gao, R AU - Friml, Jiří AU - Xiao, G ID - 12053 IS - 12 JF - The Plant Cell SN - 1040-4651 TI - Strigolactones act downstream of gibberellins to regulate fiber cell elongation and cell wall thickness in cotton (Gossypium hirsutum) VL - 34 ER - TY - JOUR AB - Directionality in the intercellular transport of the plant hormone auxin is determined by polar plasma membrane localization of PIN-FORMED (PIN) auxin transport proteins. However, apart from PIN phosphorylation at conserved motifs, no further determinants explicitly controlling polar PIN sorting decisions have been identified. Here we present Arabidopsis WAVY GROWTH 3 (WAV3) and closely related RING-finger E3 ubiquitin ligases, whose loss-of-function mutants show a striking apical-to-basal polarity switch in PIN2 localization in root meristem cells. WAV3 E3 ligases function as essential determinants for PIN polarity, acting independently from PINOID/WAG-dependent PIN phosphorylation. They antagonize ectopic deposition of de novo synthesized PIN proteins already immediately following completion of cell division, presumably via preventing PIN sorting into basal, ARF GEF-mediated trafficking. Our findings reveal an involvement of E3 ligases in the selective targeting of apically localized PINs in higher plants. AU - Konstantinova, N AU - Hörmayer, Lukas AU - Glanc, Matous AU - Keshkeih, R AU - Tan, Shutang AU - Di Donato, M AU - Retzer, K AU - Moulinier-Anzola, J AU - Schwihla, M AU - Korbei, B AU - Geisler, M AU - Friml, Jiří AU - Luschnig, C ID - 12052 JF - Nature Communications SN - 2041-1723 TI - WAVY GROWTH Arabidopsis E3 ubiquitin ligases affect apical PIN sorting decisions VL - 13 ER - TY - JOUR AB - Polar auxin transport is unique to plants and coordinates their growth and development1,2. The PIN-FORMED (PIN) auxin transporters exhibit highly asymmetrical localizations at the plasma membrane and drive polar auxin transport3,4; however, their structures and transport mechanisms remain largely unknown. Here, we report three inward-facing conformation structures of Arabidopsis thaliana PIN1: the apo state, bound to the natural auxin indole-3-acetic acid (IAA), and in complex with the polar auxin transport inhibitor N-1-naphthylphthalamic acid (NPA). The transmembrane domain of PIN1 shares a conserved NhaA fold5. In the substrate-bound structure, IAA is coordinated by both hydrophobic stacking and hydrogen bonding. NPA competes with IAA for the same site at the intracellular pocket, but with a much higher affinity. These findings inform our understanding of the substrate recognition and transport mechanisms of PINs and set up a framework for future research on directional auxin transport, one of the most crucial processes underlying plant development. AU - Yang, Z AU - Xia, J AU - Hong, J AU - Zhang, C AU - Wei, H AU - Ying, W AU - Sun, C AU - Sun, L AU - Mao, Y AU - Gao, Y AU - Tan, S AU - Friml, Jiří AU - Li, D AU - Liu, X AU - Sun, L ID - 12054 IS - 7927 JF - Nature SN - 0028-0836 TI - Structural insights into auxin recognition and efflux by Arabidopsis PIN1 VL - 609 ER - TY - JOUR AB - Autophagosomes are double-membraned vesicles that traffic harmful or unwanted cellular macromolecules to the vacuole for recycling. Although autophagosome biogenesis has been extensively studied, autophagosome maturation, i.e., delivery and fusion with the vacuole, remains largely unknown in plants. Here, we have identified an autophagy adaptor, CFS1, that directly interacts with the autophagosome marker ATG8 and localizes on both membranes of the autophagosome. Autophagosomes form normally in Arabidopsis thaliana cfs1 mutants, but their delivery to the vacuole is disrupted. CFS1’s function is evolutionarily conserved in plants, as it also localizes to the autophagosomes and plays a role in autophagic flux in the liverwort Marchantia polymorpha. CFS1 regulates autophagic flux by bridging autophagosomes with the multivesicular body-localized ESCRT-I component VPS23A, leading to the formation of amphisomes. Similar to CFS1-ATG8 interaction, disrupting the CFS1-VPS23A interaction blocks autophagic flux and renders plants sensitive to nitrogen starvation. Altogether, our results reveal a conserved vacuolar sorting hub that regulates autophagic flux in plants. AU - Zhao, Jierui AU - Bui, Mai Thu AU - Ma, Juncai AU - Künzl, Fabian AU - Picchianti, Lorenzo AU - De La Concepcion, Juan Carlos AU - Chen, Yixuan AU - Petsangouraki, Sofia AU - Mohseni, Azadeh AU - García-Leon, Marta AU - Gomez, Marta Salas AU - Giannini, Caterina AU - Gwennogan, Dubois AU - Kobylinska, Roksolana AU - Clavel, Marion AU - Schellmann, Swen AU - Jaillais, Yvon AU - Friml, Jiří AU - Kang, Byung-Ho AU - Dagdas, Yasin ID - 12121 IS - 12 JF - Journal of Cell Biology KW - Cell Biology SN - 0021-9525 TI - Plant autophagosomes mature into amphisomes prior to their delivery to the central vacuole VL - 221 ER - TY - JOUR AB - Germline determination is essential for species survival and evolution in multicellular organisms. In most flowering plants, formation of the female germline is initiated with specification of one megaspore mother cell (MMC) in each ovule; however, the molecular mechanism underlying this key event remains unclear. Here we report that spatially restricted auxin signaling promotes MMC fate in Arabidopsis. Our results show that the microRNA160 (miR160) targeted gene ARF17 (AUXIN RESPONSE FACTOR17) is required for promoting MMC specification by genetically interacting with the SPL/NZZ (SPOROCYTELESS/NOZZLE) gene. Alterations of auxin signaling cause formation of supernumerary MMCs in an ARF17- and SPL/NZZ-dependent manner. Furthermore, miR160 and ARF17 are indispensable for attaining a normal auxin maximum at the ovule apex via modulating the expression domain of PIN1 (PIN-FORMED1) auxin transporter. Our findings elucidate the mechanism by which auxin signaling promotes the acquisition of female germline cell fate in plants. AU - Huang, Jian AU - Zhao, Lei AU - Malik, Shikha AU - Gentile, Benjamin R. AU - Xiong, Va AU - Arazi, Tzahi AU - Owen, Heather A. AU - Friml, Jiří AU - Zhao, Dazhong ID - 12130 JF - Nature Communications KW - General Physics and Astronomy KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Chemistry KW - Multidisciplinary SN - 2041-1723 TI - Specification of female germline by microRNA orchestrated auxin signaling in Arabidopsis VL - 13 ER - TY - JOUR AB - Biological systems are the sum of their dynamic three-dimensional (3D) parts. Therefore, it is critical to study biological structures in 3D and at high resolution to gain insights into their physiological functions. Electron microscopy of metal replicas of unroofed cells and isolated organelles has been a key technique to visualize intracellular structures at nanometer resolution. However, many of these methods require specialized equipment and personnel to complete them. Here, we present novel accessible methods to analyze biological structures in unroofed cells and biochemically isolated organelles in 3D and at nanometer resolution, focusing on Arabidopsis clathrin-coated vesicles (CCVs). While CCVs are essential trafficking organelles, their detailed structural information is lacking due to their poor preservation when observed via classical electron microscopy protocols experiments. First, we establish a method to visualize CCVs in unroofed cells using scanning transmission electron microscopy tomography, providing sufficient resolution to define the clathrin coat arrangements. Critically, the samples are prepared directly on electron microscopy grids, removing the requirement to use extremely corrosive acids, thereby enabling the use of this method in any electron microscopy lab. Secondly, we demonstrate that this standardized sample preparation allows the direct comparison of isolated CCV samples with those visualized in cells. Finally, to facilitate the high-throughput and robust screening of metal replicated samples, we provide a deep learning analysis method to screen the “pseudo 3D” morphologies of CCVs imaged with 2D modalities. Collectively, our work establishes accessible ways to examine the 3D structure of biological samples and provide novel insights into the structure of plant CCVs. AU - Johnson, Alexander J AU - Kaufmann, Walter AU - Sommer, Christoph M AU - Costanzo, Tommaso AU - Dahhan, Dana A. AU - Bednarek, Sebastian Y. AU - Friml, Jiří ID - 12239 IS - 10 JF - Molecular Plant KW - Plant Science KW - Molecular Biology SN - 1674-2052 TI - Three-dimensional visualization of planta clathrin-coated vesicles at ultrastructural resolution VL - 15 ER - TY - JOUR AB - Much of plant development depends on cell-to-cell redistribution of the plant hormone auxin, which is facilitated by the plasma membrane (PM) localized PIN FORMED (PIN) proteins. Auxin export activity, developmental roles, subcellular trafficking, and polarity of PINs have been well studied, but their structure remains elusive besides a rough outline that they contain two groups of 5 alpha-helices connected by a large hydrophilic loop (HL). Here, we focus on the PIN1 HL as we could produce it in sufficient quantities for biochemical investigations to provide insights into its secondary structure. Circular dichroism (CD) studies revealed its nature as an intrinsically disordered protein (IDP), manifested by the increase of structure content upon thermal melting. Consistent with IDPs serving as interaction platforms, PIN1 loops homodimerize. PIN1 HL cytoplasmic overexpression in Arabidopsis disrupts early endocytic trafficking of PIN1 and PIN2 and causes defects in the cotyledon vasculature formation. In summary, we demonstrate that PIN1 HL has an intrinsically disordered nature, which must be considered to gain further structural insights. Some secondary structures may form transiently during pairing with known and yet-to-be-discovered interactors. AU - Bilanovičová, V AU - Rýdza, N AU - Koczka, L AU - Hess, M AU - Feraru, E AU - Friml, Jiří AU - Nodzyński, T ID - 11489 IS - 11 JF - International Journal of Molecular Sciences SN - 1422-0067 TI - The hydrophilic loop of Arabidopsis PIN1 auxin efflux carrier harbors hallmarks of an intrinsically disordered protein VL - 23 ER - TY - JOUR AB - The phytohormone auxin is the major coordinative signal in plant development1, mediating transcriptional reprogramming by a well-established canonical signalling pathway. TRANSPORT INHIBITOR RESPONSE 1 (TIR1)/AUXIN-SIGNALING F-BOX (AFB) auxin receptors are F-box subunits of ubiquitin ligase complexes. In response to auxin, they associate with Aux/IAA transcriptional repressors and target them for degradation via ubiquitination2,3. Here we identify adenylate cyclase (AC) activity as an additional function of TIR1/AFB receptors across land plants. Auxin, together with Aux/IAAs, stimulates cAMP production. Three separate mutations in the AC motif of the TIR1 C-terminal region, all of which abolish the AC activity, each render TIR1 ineffective in mediating gravitropism and sustained auxin-induced root growth inhibition, and also affect auxin-induced transcriptional regulation. These results highlight the importance of TIR1/AFB AC activity in canonical auxin signalling. They also identify a unique phytohormone receptor cassette combining F-box and AC motifs, and the role of cAMP as a second messenger in plants. AU - Qi, Linlin AU - Kwiatkowski, Mateusz AU - Chen, Huihuang AU - Hörmayer, Lukas AU - Sinclair, Scott A AU - Zou, Minxia AU - del Genio, Charo I. AU - Kubeš, Martin F. AU - Napier, Richard AU - Jaworski, Krzysztof AU - Friml, Jiří ID - 12144 IS - 7934 JF - Nature SN - 0028-0836 TI - Adenylate cyclase activity of TIR1/AFB auxin receptors in plants VL - 611 ER - TY - JOUR AB - Plant root architecture flexibly adapts to changing nitrate (NO3−) availability in the soil; however, the underlying molecular mechanism of this adaptive development remains under-studied. To explore the regulation of NO3−-mediated root growth, we screened for low-nitrate-resistant mutant (lonr) and identified mutants that were defective in the NAC transcription factor NAC075 (lonr1) as being less sensitive to low NO3− in terms of primary root growth. We show that NAC075 is a mobile transcription factor relocating from the root stele tissues to the endodermis based on NO3− availability. Under low-NO3− availability, the kinase CBL-interacting protein kinase 1 (CIPK1) is activated, and it phosphorylates NAC075, restricting its movement from the stele, which leads to the transcriptional regulation of downstream target WRKY53, consequently leading to adapted root architecture. Our work thus identifies an adaptive mechanism involving translocation of transcription factor based on nutrient availability and leading to cell-specific reprogramming of plant root growth. AU - Xiao, Huixin AU - Hu, Yumei AU - Wang, Yaping AU - Cheng, Jinkui AU - Wang, Jinyi AU - Chen, Guojingwei AU - Li, Qian AU - Wang, Shuwei AU - Wang, Yalu AU - Wang, Shao-Shuai AU - Wang, Yi AU - Xuan, Wei AU - Li, Zhen AU - Guo, Yan AU - Gong, Zhizhong AU - Friml, Jiří AU - Zhang, Jing ID - 12120 IS - 23 JF - Developmental Cell KW - Developmental Biology KW - Cell Biology KW - General Biochemistry KW - Genetics and Molecular Biology KW - Molecular Biology SN - 1534-5807 TI - Nitrate availability controls translocation of the transcription factor NAC075 for cell-type-specific reprogramming of root growth VL - 57 ER - TY - JOUR AB - The phytohormone auxin triggers transcriptional reprogramming through a well-characterized perception machinery in the nucleus. By contrast, mechanisms that underlie fast effects of auxin, such as the regulation of ion fluxes, rapid phosphorylation of proteins or auxin feedback on its transport, remain unclear1,2,3. Whether auxin-binding protein 1 (ABP1) is an auxin receptor has been a source of debate for decades1,4. Here we show that a fraction of Arabidopsis thaliana ABP1 is secreted and binds auxin specifically at an acidic pH that is typical of the apoplast. ABP1 and its plasma-membrane-localized partner, transmembrane kinase 1 (TMK1), are required for the auxin-induced ultrafast global phospho-response and for downstream processes that include the activation of H+-ATPase and accelerated cytoplasmic streaming. abp1 and tmk mutants cannot establish auxin-transporting channels and show defective auxin-induced vasculature formation and regeneration. An ABP1(M2X) variant that lacks the capacity to bind auxin is unable to complement these defects in abp1 mutants. These data indicate that ABP1 is the auxin receptor for TMK1-based cell-surface signalling, which mediates the global phospho-response and auxin canalization. AU - Friml, Jiří AU - Gallei, Michelle C AU - Gelová, Zuzana AU - Johnson, Alexander J AU - Mazur, Ewa AU - Monzer, Aline AU - Rodriguez Solovey, Lesia AU - Roosjen, Mark AU - Verstraeten, Inge AU - Živanović, Branka D. AU - Zou, Minxia AU - Fiedler, Lukas AU - Giannini, Caterina AU - Grones, Peter AU - Hrtyan, Mónika AU - Kaufmann, Walter AU - Kuhn, Andre AU - Narasimhan, Madhumitha AU - Randuch, Marek AU - Rýdza, Nikola AU - Takahashi, Koji AU - Tan, Shutang AU - Teplova, Anastasiia AU - Kinoshita, Toshinori AU - Weijers, Dolf AU - Rakusová, Hana ID - 12291 IS - 7927 JF - Nature SN - 0028-0836 TI - ABP1–TMK auxin perception for global phosphorylation and auxin canalization VL - 609 ER - TY - THES AB - Plant growth and development is well known to be both, flexible and dynamic. The high capacity for post-embryonic organ formation and tissue regeneration requires tightly regulated intercellular communication and coordinated tissue polarization. One of the most important drivers for patterning and polarity in plant development is the phytohormone auxin. Auxin has the unique characteristic to establish polarized channels for its own active directional cell to cell transport. This fascinating phenomenon is called auxin canalization. Those auxin transport channels are characterized by the expression and polar, subcellular localization of PIN auxin efflux carriers. PIN proteins have the ability to dynamically change their localization and auxin itself can affect this by interfering with trafficking. Most of the underlying molecular mechanisms of canalization still remain enigmatic. What is known so far is that canonical auxin signaling is indispensable but also other non-canonical signaling components are thought to play a role. In order to shed light into the mysteries auf auxin canalization this study revisits the branches of auxin signaling in detail. Further a new auxin analogue, PISA, is developed which triggers auxin-like responses but does not directly activate canonical transcriptional auxin signaling. We revisit the direct auxin effect on PIN trafficking where we found that, contradictory to previous observations, auxin is very specifically promoting endocytosis of PIN2 but has no overall effect on endocytosis. Further, we evaluate which cellular processes related to PIN subcellular dynamics are involved in the establishment of auxin conducting channels and the formation of vascular tissue. We are re-evaluating the function of AUXIN BINDING PROTEIN 1 (ABP1) and provide a comprehensive picture about its developmental phneotypes and involvement in auxin signaling and canalization. Lastly, we are focusing on the crosstalk between the hormone strigolactone (SL) and auxin and found that SL is interfering with essentially all processes involved in auxin canalization in a non-transcriptional manner. Lastly we identify a new way of SL perception and signaling which is emanating from mitochondria, is independent of canonical SL signaling and is modulating primary root growth. AU - Gallei, Michelle C ID - 11626 SN - 2663-337X TI - Auxin and strigolactone non-canonical signaling regulating development in Arabidopsis thaliana ER - TY - JOUR AB - The phytohormone auxin is the major growth regulator governing tropic responses including gravitropism. Auxin build-up at the lower side of stimulated shoots promotes cell expansion, whereas in roots it inhibits growth, leading to upward shoot bending and downward root bending, respectively. Yet it remains an enigma how the same signal can trigger such opposite cellular responses. In this review, we discuss several recent unexpected insights into the mechanisms underlying auxin regulation of growth, challenging several existing models. We focus on the divergent mechanisms of apoplastic pH regulation in shoots and roots revisiting the classical Acid Growth Theory and discuss coordinated involvement of multiple auxin signaling pathways. From this emerges a more comprehensive, updated picture how auxin regulates growth. AU - Li, Lanxin AU - Gallei, Michelle C AU - Friml, Jiří ID - 10411 IS - 5 JF - Trends in Plant Science SN - 1360-1385 TI - Bending to auxin: Fast acid growth for tropisms VL - 27 ER - TY - JOUR AB - Ustilago maydis is a biotrophic phytopathogenic fungus that causes corn smut disease. As a well-established model system, U. maydis is genetically fully accessible with large omics datasets available and subject to various biological questions ranging from DNA-repair, RNA-transport, and protein secretion to disease biology. For many genetic approaches, tight control of transgene regulation is important. Here we established an optimised version of the Tetracycline-ON (TetON) system for U. maydis. We demonstrate the Tetracycline concentration-dependent expression of fluorescent protein transgenes and the system’s suitability for the induced expression of the toxic protein BCL2 Associated X-1 (Bax1). The Golden Gate compatible vector system contains a native minimal promoter from the mating factor a-1 encoding gene, mfa with ten copies of the tet-regulated operator (tetO) and a codon optimised Tet-repressor (tetR*) which is translationally fused to the native transcriptional corepressor Mql1 (UMAG_05501). The metabolism-independent transcriptional regulator system is functional both, in liquid culture as well as on solid media in the presence of the inducer and can become a useful tool for toxin-antitoxin studies, identification of antifungal proteins, and to study functions of toxic gene products in Ustilago maydis. AU - Ingole, Kishor D. AU - Nagarajan, Nithya AU - Uhse, Simon AU - Giannini, Caterina AU - Djamei, Armin ID - 13240 JF - Frontiers in Fungal Biology TI - Tetracycline-controlled (TetON) gene expression system for the smut fungus Ustilago maydis VL - 3 ER - TY - CHAP AB - Tropisms are among the most important growth responses for plant adaptation to the surrounding environment. One of the most common tropisms is root gravitropism. Root gravitropism enables the plant to anchor securely to the soil enabling the absorption of water and nutrients. Most of the knowledge related to the plant gravitropism has been acquired from the flowering plants, due to limited research in non-seed plants. Limited research on non-seed plants is due in large part to the lack of standard research methods. Here, we describe the experimental methods to evaluate gravitropism in representative non-seed plant species, including the non-vascular plant moss Physcomitrium patens, the early diverging extant vascular plant lycophyte Selaginella moellendorffii and fern Ceratopteris richardii. In addition, we introduce the methods used for statistical analysis of the root gravitropism in non-seed plant species. AU - Zhang, Yuzhou AU - Li, Lanxin AU - Friml, Jiří ED - Blancaflor, Elison B ID - 10267 SN - 978-1-0716-1676-5 T2 - Plant Gravitropism TI - Evaluation of gravitropism in non-seed plants VL - 2368 ER - TY - CHAP AB - The analysis of dynamic cellular processes such as plant cytokinesis stands and falls with live-cell time-lapse confocal imaging. Conventional approaches to time-lapse imaging of cell division in Arabidopsis root tips are tedious and have low throughput. Here, we describe a protocol for long-term time-lapse simultaneous imaging of multiple root tips on a vertical-stage confocal microscope with automated root tracking. We also provide modifications of the basic protocol to implement this imaging method in the analysis of genetic, pharmacological or laser ablation wounding-mediated experimental manipulations. Our method dramatically improves the efficiency of cell division time-lapse imaging by increasing the throughput, while reducing the person-hour requirements of such experiments. AU - Hörmayer, Lukas AU - Friml, Jiří AU - Glanc, Matous ID - 10268 SN - 1064-3745 T2 - Plant Cell Division TI - Automated time-lapse imaging and manipulation of cell divisions in Arabidopsis roots by vertical-stage confocal microscopy VL - 2382 ER - TY - JOUR AB - Cell and tissue polarization is fundamental for plant growth and morphogenesis. The polar, cellular localization of Arabidopsis PIN‐FORMED (PIN) proteins is crucial for their function in directional auxin transport. The clustering of PIN polar cargoes within the plasma membrane has been proposed to be important for the maintenance of their polar distribution. However, the more detailed features of PIN clusters and the cellular requirements of cargo clustering remain unclear. Here, we characterized PIN clusters in detail by means of multiple advanced microscopy and quantification methods, such as 3D quantitative imaging or freeze‐fracture replica labeling. The size and aggregation types of PIN clusters were determined by electron microscopy at the nanometer level at different polar domains and at different developmental stages, revealing a strong preference for clustering at the polar domains. Pharmacological and genetic studies revealed that PIN clusters depend on phosphoinositol pathways, cytoskeletal structures and specific cell‐wall components as well as connections between the cell wall and the plasma membrane. This study identifies the role of different cellular processes and structures in polar cargo clustering and provides initial mechanistic insight into the maintenance of polarity in plants and other systems. AU - Li, Hongjiang AU - von Wangenheim, Daniel AU - Zhang, Xixi AU - Tan, Shutang AU - Darwish-Miranda, Nasser AU - Naramoto, Satoshi AU - Wabnik, Krzysztof T AU - de Rycke, Riet AU - Kaufmann, Walter AU - Gütl, Daniel J AU - Tejos, Ricardo AU - Grones, Peter AU - Ke, Meiyu AU - Chen, Xu AU - Dettmer, Jan AU - Friml, Jiří ID - 8582 IS - 1 JF - New Phytologist SN - 0028646X TI - Cellular requirements for PIN polar cargo clustering in Arabidopsis thaliana VL - 229 ER - TY - JOUR AB - The leaf is a crucial organ evolved with remarkable morphological diversity to maximize plant photosynthesis. The leaf shape is a key trait that affects photosynthesis, flowering rates, disease resistance, and yield. Although many genes regulating leaf development have been identified in the past years, the precise regulatory architecture underlying the generation of diverse leaf shapes remains to be elucidated. We used cotton as a reference model to probe the genetic framework underlying divergent leaf forms. Comparative transcriptome analysis revealed that the GhARF16‐1 and GhKNOX2‐1 genes might be potential regulators of leaf shape. We functionally characterized the auxin‐responsive factor ARF16‐1 acting upstream of GhKNOX2‐1 to determine leaf morphology in cotton. The transcription of GhARF16‐1 was significantly higher in lobed‐leaved cotton than in smooth‐leaved cotton. Furthermore, the overexpression of GhARF16‐1 led to the upregulation of GhKNOX2‐1 and resulted in more and deeper serrations in cotton leaves, similar to the leaf shape of cotton plants overexpressing GhKNOX2‐1. We found that GhARF16‐1 specifically bound to the promoter of GhKNOX2‐1 to induce its expression. The heterologous expression of GhARF16‐1 and GhKNOX2‐1 in Arabidopsis led to lobed and curly leaves, and a genetic analysis revealed that GhKNOX2‐1 is epistatic to GhARF16‐1 in Arabidopsis, suggesting that the GhARF16‐1 and GhKNOX2‐1 interaction paradigm also functions to regulate leaf shape in Arabidopsis. To our knowledge, our results uncover a novel mechanism by which auxin, through the key component ARF16‐1 and its downstream‐activated gene KNOX2‐1, determines leaf morphology in eudicots. AU - He, P AU - Zhang, Yuzhou AU - Li, H AU - Fu, X AU - Shang, H AU - Zou, C AU - Friml, Jiří AU - Xiao, G ID - 8606 IS - 3 JF - Plant Biotechnology Journal SN - 1467-7644 TI - GhARF16-1 modulates leaf development by transcriptionally regulating the GhKNOX2-1 gene in cotton VL - 19 ER - TY - JOUR AB - The phytohormone auxin plays a central role in shaping plant growth and development. With decades of genetic and biochemical studies, numerous core molecular components and their networks, underlying auxin biosynthesis, transport, and signaling, have been identified. Notably, protein phosphorylation, catalyzed by kinases and oppositely hydrolyzed by phosphatases, has been emerging to be a crucial type of post-translational modification, regulating physiological and developmental auxin output at all levels. In this review, we comprehensively discuss earlier and recent advances in our understanding of genetics, biochemistry, and cell biology of the kinases and phosphatases participating in auxin action. We provide insights into the mechanisms by which reversible protein phosphorylation defines developmental auxin responses, discuss current challenges, and provide our perspectives on future directions involving the integration of the control of protein phosphorylation into the molecular auxin network. AU - Tan, Shutang AU - Luschnig, Christian AU - Friml, Jiří ID - 8992 IS - 1 JF - Molecular Plant SN - 16742052 TI - Pho-view of auxin: Reversible protein phosphorylation in auxin biosynthesis, transport and signaling VL - 14 ER - TY - JOUR AB - N-1-naphthylphthalamic acid (NPA) is a key inhibitor of directional (polar) transport of the hormone auxin in plants. For decades, it has been a pivotal tool in elucidating the unique polar auxin transport-based processes underlying plant growth and development. Its exact mode of action has long been sought after and is still being debated, with prevailing mechanistic schemes describing only indirect connections between NPA and the main transporters responsible for directional transport, namely PIN auxin exporters. Here we present data supporting a model in which NPA associates with PINs in a more direct manner than hitherto postulated. We show that NPA inhibits PIN activity in a heterologous oocyte system and that expression of NPA-sensitive PINs in plant, yeast, and oocyte membranes leads to specific saturable NPA binding. We thus propose that PINs are a bona fide NPA target. This offers a straightforward molecular basis for NPA inhibition of PIN-dependent auxin transport and a logical parsimonious explanation for the known physiological effects of NPA on plant growth, as well as an alternative hypothesis to interpret past and future results. We also introduce PIN dimerization and describe an effect of NPA on this, suggesting that NPA binding could be exploited to gain insights into structural aspects of PINs related to their transport mechanism. AU - Abas, Lindy AU - Kolb, Martina AU - Stadlmann, Johannes AU - Janacek, Dorina P. AU - Lukic, Kristina AU - Schwechheimer, Claus AU - Sazanov, Leonid A AU - Mach, Lukas AU - Friml, Jiří AU - Hammes, Ulrich Z. ID - 8993 IS - 1 JF - PNAS SN - 00278424 TI - Naphthylphthalamic acid associates with and inhibits PIN auxin transporters VL - 118 ER - TY - JOUR AB - Auxin is a key regulator of plant growth and development. Local auxin biosynthesis and intercellular transport generates regional gradients in the root that are instructive for processes such as specification of developmental zones that maintain root growth and tropic responses. Here we present a toolbox to study auxin-mediated root development that features: (i) the ability to control auxin synthesis with high spatio-temporal resolution and (ii) single-cell nucleus tracking and morphokinetic analysis infrastructure. Integration of these two features enables cutting-edge analysis of root development at single-cell resolution based on morphokinetic parameters under normal growth conditions and during cell-type-specific induction of auxin biosynthesis. We show directional auxin flow in the root and refine the contributions of key players in this process. In addition, we determine the quantitative kinetics of Arabidopsis root meristem skewing, which depends on local auxin gradients but does not require PIN2 and AUX1 auxin transporter activities. Beyond the mechanistic insights into root development, the tools developed here will enable biologists to study kinetics and morphology of various critical processes at the single cell-level in whole organisms. AU - Hu, Yangjie AU - Omary, Moutasem AU - Hu, Yun AU - Doron, Ohad AU - Hörmayer, Lukas AU - Chen, Qingguo AU - Megides, Or AU - Chekli, Ori AU - Ding, Zhaojun AU - Friml, Jiří AU - Zhao, Yunde AU - Tsarfaty, Ilan AU - Shani, Eilon ID - 9254 JF - Nature Communications TI - Cell kinetics of auxin transport and activity in Arabidopsis root growth and skewing VL - 12 ER - TY - JOUR AB - Endoplasmic reticulum–plasma membrane contact sites (ER–PM CS) play fundamental roles in all eukaryotic cells. Arabidopsis thaliana mutants lacking the ER–PM protein tether synaptotagmin1 (SYT1) exhibit decreased PM integrity under multiple abiotic stresses, such as freezing, high salt, osmotic stress, and mechanical damage. Here, we show that, together with SYT1, the stress-induced SYT3 is an ER–PM tether that also functions in maintaining PM integrity. The ER–PM CS localization of SYT1 and SYT3 is dependent on PM phosphatidylinositol-4-phosphate and is regulated by abiotic stress. Lipidomic analysis revealed that cold stress increased the accumulation of diacylglycerol at the PM in a syt1/3 double mutant relative to wild-type while the levels of most glycerolipid species remain unchanged. In addition, the SYT1-green fluorescent protein fusion preferentially binds diacylglycerol in vivo with little affinity for polar glycerolipids. Our work uncovers a SYT-dependent mechanism of stress adaptation counteracting the detrimental accumulation of diacylglycerol at the PM produced during episodes of abiotic stress. AU - Ruiz-Lopez, N AU - Pérez-Sancho, J AU - Esteban Del Valle, A AU - Haslam, RP AU - Vanneste, S AU - Catalá, R AU - Perea-Resa, C AU - Van Damme, D AU - García-Hernández, S AU - Albert, A AU - Vallarino, J AU - Lin, J AU - Friml, Jiří AU - Macho, AP AU - Salinas, J AU - Rosado, A AU - Napier, JA AU - Amorim-Silva, V AU - Botella, MA ID - 9443 IS - 7 JF - Plant Cell SN - 1040-4651 TI - Synaptotagmins at the endoplasmic reticulum-plasma membrane contact sites maintain diacylglycerol homeostasis during abiotic stress VL - 33 ER - TY - JOUR AB - To overcome nitrogen deficiency, legume roots establish symbiotic interactions with nitrogen-fixing rhizobia that is fostered in specialized organs (nodules). Similar to other organs, nodule formation is determined by a local maximum of the phytohormone auxin at the primordium site. However, how auxin regulates nodule development remains poorly understood. Here, we found that in soybean, (Glycine max), dynamic auxin transport driven by PIN-FORMED (PIN) transporter GmPIN1 is involved in nodule primordium formation. GmPIN1 was specifically expressed in nodule primordium cells and GmPIN1 was polarly localized in these cells. Two nodulation regulators, (iso)flavonoids trigger expanded distribution of GmPIN1b to root cortical cells, and cytokinin rearranges GmPIN1b polarity. Gmpin1abc triple mutants generated with CRISPR-Cas9 showed impaired establishment of auxin maxima in nodule meristems and aberrant divisions in the nodule primordium cells. Moreover, overexpression of GmPIN1 suppressed nodule primordium initiation. GmPIN9d, an ortholog of Arabidopsis thaliana PIN2, acts together with GmPIN1 later in nodule development to acropetally transport auxin in vascular bundles, fine-tuning the auxin supply for nodule enlargement. Our findings reveal how PIN-dependent auxin transport modulates different aspects of soybean nodule development and suggest that establishment of auxin gradient is a prerequisite for the proper interaction between legumes and rhizobia. AU - Gao, Z AU - Chen, Z AU - Cui, Y AU - Ke, M AU - Xu, H AU - Xu, Q AU - Chen, J AU - Li, Y AU - Huang, L AU - Zhao, H AU - Huang, D AU - Mai, S AU - Xu, T AU - Liu, X AU - Li, S AU - Guan, Y AU - Yang, W AU - Friml, Jiří AU - Petrášek, J AU - Zhang, J AU - Chen, X ID - 9657 IS - 9 JF - Plant Cell SN - 1040-4651 TI - GmPIN-dependent polar auxin transport is involved in soybean nodule development VL - 33 ER - TY - JOUR AB - Tropisms, growth responses to environmental stimuli such as light or gravity, are spectacular examples of adaptive plant development. The plant hormone auxin serves as a major coordinative signal. The PIN auxin exporters, through their dynamic polar subcellular localizations, redirect auxin fluxes in response to environmental stimuli and the resulting auxin gradients across organs underly differential cell elongation and bending. In this review, we discuss recent advances concerning regulations of PIN polarity during tropisms, focusing on PIN phosphorylation and trafficking. We also cover how environmental cues regulate PIN actions during tropisms, and a crucial role of auxin feedback on PIN polarity during bending termination. Finally, the interactions between different tropisms are reviewed to understand plant adaptive growth in the natural environment. AU - Han, Huibin AU - Adamowski, Maciek AU - Qi, Linlin AU - Alotaibi, SS AU - Friml, Jiří ID - 9656 IS - 2 JF - New Phytologist SN - 0028-646x TI - PIN-mediated polar auxin transport regulations in plant tropic responses VL - 232 ER - TY - JOUR AB - Roots are composed of different root types and, in the dicotyledonous Arabidopsis, typically consist of a primary root that branches into lateral roots. Adventitious roots emerge from non-root tissue and are formed upon wounding or other types of abiotic stress. Here, we investigated adventitious root (AR) formation in Arabidopsis hypocotyls under conditions of altered abscisic acid (ABA) signaling. Exogenously applied ABA suppressed AR formation at 0.25 µM or higher doses. AR formation was less sensitive to the synthetic ABA analog pyrabactin (PB). However, PB was a more potent inhibitor at concentrations above 1 µM, suggesting that it was more selective in triggering a root inhibition response. Analysis of a series of phosphonamide and phosphonate pyrabactin analogs suggested that adventitious root formation and lateral root branching are differentially regulated by ABA signaling. ABA biosynthesis and signaling mutants affirmed a general inhibitory role of ABA and point to PYL1 and PYL2 as candidate ABA receptors that regulate AR inhibition. AU - Zeng, Yinwei AU - Verstraeten, Inge AU - Trinh, Hoang Khai AU - Heugebaert, Thomas AU - Stevens, Christian V. AU - Garcia-Maquilon, Irene AU - Rodriguez, Pedro L. AU - Vanneste, Steffen AU - Geelen, Danny ID - 9909 IS - 8 JF - Genes TI - Arabidopsis hypocotyl adventitious root formation is suppressed by ABA signaling VL - 12 ER - TY - JOUR AB - Advanced transcriptome sequencing has revealed that the majority of eukaryotic genes undergo alternative splicing (AS). Nonetheless, little effort has been dedicated to investigating the functional relevance of particular splicing events, even those in the key developmental and hormonal regulators. Combining approaches of genetics, biochemistry and advanced confocal microscopy, we describe the impact of alternative splicing on the PIN7 gene in the model plant Arabidopsis thaliana. PIN7 encodes a polarly localized transporter for the phytohormone auxin and produces two evolutionarily conserved transcripts, PIN7a and PIN7b. PIN7a and PIN7b, differing in a four amino acid stretch, exhibit almost identical expression patterns and subcellular localization. We reveal that they are closely associated and mutually influence each other's mobility within the plasma membrane. Phenotypic complementation tests indicate that the functional contribution of PIN7b per se is minor, but it markedly reduces the prominent PIN7a activity, which is required for correct seedling apical hook formation and auxin-mediated tropic responses. Our results establish alternative splicing of the PIN family as a conserved, functionally relevant mechanism, revealing an additional regulatory level of auxin-mediated plant development. AU - Kashkan, Ivan AU - Hrtyan, Mónika AU - Retzer, Katarzyna AU - Humpolíčková, Jana AU - Jayasree, Aswathy AU - Filepová, Roberta AU - Vondráková, Zuzana AU - Simon, Sibu AU - Rombaut, Debbie AU - Jacobs, Thomas B. AU - Frilander, Mikko J. AU - Hejátko, Jan AU - Friml, Jiří AU - Petrášek, Jan AU - Růžička, Kamil ID - 10282 JF - New Phytologist SN - 0028-646X TI - Mutually opposing activity of PIN7 splicing isoforms is required for auxin-mediated tropic responses in Arabidopsis thaliana VL - 233 ER - TY - JOUR AB - Strigolactones (SLs) are carotenoid-derived plant hormones that control shoot branching and communications between host plants and symbiotic fungi or root parasitic plants. Extensive studies have identified the key components participating in SL biosynthesis and signalling, whereas the catabolism or deactivation of endogenous SLs in planta remains largely unknown. Here, we report that the Arabidopsis carboxylesterase 15 (AtCXE15) and its orthologues function as efficient hydrolases of SLs. We show that overexpression of AtCXE15 promotes shoot branching by dampening SL-inhibited axillary bud outgrowth. We further demonstrate that AtCXE15 could bind and efficiently hydrolyse SLs both in vitro and in planta. We also provide evidence that AtCXE15 is capable of catalysing hydrolysis of diverse SL analogues and that such CXE15-dependent catabolism of SLs is evolutionarily conserved in seed plants. These results disclose a catalytic mechanism underlying homoeostatic regulation of SLs in plants, which also provides a rational approach to spatial-temporally manipulate the endogenous SLs and thus architecture of crops and ornamental plants. AU - Xu, Enjun AU - Chai, Liang AU - Zhang, Shiqi AU - Yu, Ruixue AU - Zhang, Xixi AU - Xu, Chongyi AU - Hu, Yuxin ID - 10326 JF - Nature Plants TI - Catabolism of strigolactones by a carboxylesterase VL - 7 ER - TY - JOUR AB - The quality control system for messenger RNA (mRNA) is fundamental for cellular activities in eukaryotes. To elucidate the molecular mechanism of 3'-Phosphoinositide-Dependent Protein Kinase1 (PDK1), a master regulator that is essential throughout eukaryotic growth and development, we employed a forward genetic approach to screen for suppressors of the loss-of-function T-DNA insertion double mutant pdk1.1 pdk1.2 in Arabidopsis thaliana. Notably, the severe growth attenuation of pdk1.1 pdk1.2 was rescued by sop21 (suppressor of pdk1.1 pdk1.2), which harbours a loss-of-function mutation in PELOTA1 (PEL1). PEL1 is a homologue of mammalian PELOTA and yeast (Saccharomyces cerevisiae) DOM34p, which each form a heterodimeric complex with the GTPase HBS1 (HSP70 SUBFAMILY B SUPPRESSOR1, also called SUPERKILLER PROTEIN7, SKI7), a protein that is responsible for ribosomal rescue and thereby assures the quality and fidelity of mRNA molecules during translation. Genetic analysis further revealed that a dysfunctional PEL1-HBS1 complex failed to degrade the T-DNA-disrupted PDK1 transcripts, which were truncated but functional, and thus rescued the growth and developmental defects of pdk1.1 pdk1.2. Our studies demonstrated the functionality of a homologous PELOTA-HBS1 complex and identified its essential regulatory role in plants, providing insights into the mechanism of mRNA quality control. AU - Kong, W AU - Tan, Shutang AU - Zhao, Q AU - Lin, DL AU - Xu, ZH AU - Friml, Jiří AU - Xue, HW ID - 9368 IS - 4 JF - Plant Physiology SN - 0032-0889 TI - mRNA surveillance complex PELOTA-HBS1 eegulates phosphoinositide-sependent protein kinase1 and plant growth VL - 186 ER - TY - JOUR AB - Polar subcellular localization of the PIN exporters of the phytohormone auxin is a key determinant of directional, intercellular auxin transport and thus a central topic of both plant cell and developmental biology. Arabidopsis mutants lacking PID, a kinase that phosphorylates PINs, or the MAB4/MEL proteins of unknown molecular function display PIN polarity defects and phenocopy pin mutants, but mechanistic insights into how these factors convey PIN polarity are missing. Here, by combining protein biochemistry with quantitative live-cell imaging, we demonstrate that PINs, MAB4/MELs, and AGC kinases interact in the same complex at the plasma membrane. MAB4/MELs are recruited to the plasma membrane by the PINs and in concert with the AGC kinases maintain PIN polarity through limiting lateral diffusion-based escape of PINs from the polar domain. The PIN-MAB4/MEL-PID protein complex has self-reinforcing properties thanks to positive feedback between AGC kinase-mediated PIN phosphorylation and MAB4/MEL recruitment. We thus uncover the molecular mechanism by which AGC kinases and MAB4/MEL proteins regulate PIN localization and plant development. AU - Glanc, Matous AU - Van Gelderen, K AU - Hörmayer, Lukas AU - Tan, Shutang AU - Naramoto, S AU - Zhang, Xixi AU - Domjan, David AU - Vcelarova, L AU - Hauschild, Robert AU - Johnson, Alexander J AU - de Koning, E AU - van Dop, M AU - Rademacher, E AU - Janson, S AU - Wei, X AU - Molnar, Gergely AU - Fendrych, Matyas AU - De Rybel, B AU - Offringa, R AU - Friml, Jiří ID - 9290 IS - 9 JF - Current Biology SN - 0960-9822 TI - AGC kinases and MAB4/MEL proteins maintain PIN polarity by limiting lateral diffusion in plant cells VL - 31 ER - TY - JOUR AB - Plants are able to orient their growth according to gravity, which ultimately controls both shoot and root architecture.1 Gravitropism is a dynamic process whereby gravistimulation induces the asymmetric distribution of the plant hormone auxin, leading to asymmetric growth, organ bending, and subsequent reset of auxin distribution back to the original pre-gravistimulation situation.1, 2, 3 Differential auxin accumulation during the gravitropic response depends on the activity of polarly localized PIN-FORMED (PIN) auxin-efflux carriers.1, 2, 3, 4 In particular, the timing of this dynamic response is regulated by PIN2,5,6 but the underlying molecular mechanisms are poorly understood. Here, we show that MEMBRANE ASSOCIATED KINASE REGULATOR2 (MAKR2) controls the pace of the root gravitropic response. We found that MAKR2 is required for the PIN2 asymmetry during gravitropism by acting as a negative regulator of the cell-surface signaling mediated by the receptor-like kinase TRANSMEMBRANE KINASE1 (TMK1).2,7, 8, 9, 10 Furthermore, we show that the MAKR2 inhibitory effect on TMK1 signaling is antagonized by auxin itself, which triggers rapid MAKR2 membrane dissociation in a TMK1-dependent manner. Our findings suggest that the timing of the root gravitropic response is orchestrated by the reversible inhibition of the TMK1 signaling pathway at the cell surface. AU - Marquès-Bueno, MM AU - Armengot, L AU - Noack, LC AU - Bareille, J AU - Rodriguez Solovey, Lesia AU - Platre, MP AU - Bayle, V AU - Liu, M AU - Opdenacker, D AU - Vanneste, S AU - Möller, BK AU - Nimchuk, ZL AU - Beeckman, T AU - Caño-Delgado, AI AU - Friml, Jiří AU - Jaillais, Y ID - 8824 IS - 1 JF - Current Biology SN - 0960-9822 TI - Auxin-regulated reversible inhibition of TMK1 signaling by MAKR2 modulates the dynamics of root gravitropism VL - 31 ER - TY - JOUR AB - • The phenylpropanoid pathway serves a central role in plant metabolism, providing numerous compounds involved in diverse physiological processes. Most carbon entering the pathway is incorporated into lignin. Although several phenylpropanoid pathway mutants show seedling growth arrest, the role for lignin in seedling growth and development is unexplored. • We use complementary pharmacological and genetic approaches to block CINNAMATE‐4‐HYDROXYLASE (C4H) functionality in Arabidopsis seedlings and a set of molecular and biochemical techniques to investigate the underlying phenotypes. • Blocking C4H resulted in reduced lateral rooting and increased adventitious rooting apically in the hypocotyl. These phenotypes coincided with an inhibition in auxin transport. The upstream accumulation in cis‐cinnamic acid was found to likely cause polar auxin transport inhibition. Conversely, a downstream depletion in lignin perturbed phloem‐mediated auxin transport. Restoring lignin deposition effectively reestablished phloem transport and, accordingly, auxin homeostasis. • Our results show that the accumulation of bioactive intermediates and depletion in lignin jointly cause the aberrant phenotypes upon blocking C4H, and demonstrate that proper deposition of lignin is essential for the establishment of auxin distribution in seedlings. Our data position the phenylpropanoid pathway and lignin in a new physiological framework, consolidating their importance in plant growth and development. AU - El Houari, I AU - Van Beirs, C AU - Arents, HE AU - Han, Huibin AU - Chanoca, A AU - Opdenacker, D AU - Pollier, J AU - Storme, V AU - Steenackers, W AU - Quareshy, M AU - Napier, R AU - Beeckman, T AU - Friml, Jiří AU - De Rybel, B AU - Boerjan, W AU - Vanholme, B ID - 9288 IS - 6 JF - New Phytologist SN - 0028-646x TI - Seedling developmental defects upon blocking CINNAMATE-4-HYDROXYLASE are caused by perturbations in auxin transport VL - 230 ER - TY - JOUR AB - To adapt to the diverse array of biotic and abiotic cues, plants have evolved sophisticated mechanisms to sense changes in environmental conditions and modulate their growth. Growth-promoting hormones and defence signalling fine tune plant development antagonistically. During host-pathogen interactions, this defence-growth trade-off is mediated by the counteractive effects of the defence hormone salicylic acid (SA) and the growth hormone auxin. Here we revealed an underlying mechanism of SA regulating auxin signalling by constraining the plasma membrane dynamics of PIN2 auxin efflux transporter in Arabidopsis thaliana roots. The lateral diffusion of PIN2 proteins is constrained by SA signalling, during which PIN2 proteins are condensed into hyperclusters depending on REM1.2-mediated nanodomain compartmentalisation. Furthermore, membrane nanodomain compartmentalisation by SA or Remorin (REM) assembly significantly suppressed clathrin-mediated endocytosis. Consequently, SA-induced heterogeneous surface condensation disrupted asymmetric auxin distribution and the resultant gravitropic response. Our results demonstrated a defence-growth trade-off mechanism by which SA signalling crosstalked with auxin transport by concentrating membrane-resident PIN2 into heterogeneous compartments. AU - Ke, M AU - Ma, Z AU - Wang, D AU - Sun, Y AU - Wen, C AU - Huang, D AU - Chen, Z AU - Yang, L AU - Tan, Shutang AU - Li, R AU - Friml, Jiří AU - Miao, Y AU - Chen, X ID - 8608 IS - 2 JF - New Phytologist SN - 0028-646x TI - Salicylic acid regulates PIN2 auxin transporter hyper-clustering and root gravitropic growth via Remorin-dependent lipid nanodomain organization in Arabidopsis thaliana VL - 229 ER - TY - JOUR AB - In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field. AU - Klionsky, Daniel J. AU - Abdel-Aziz, Amal Kamal AU - Abdelfatah, Sara AU - Abdellatif, Mahmoud AU - Abdoli, Asghar AU - Abel, Steffen AU - Abeliovich, Hagai AU - Abildgaard, Marie H. AU - Abudu, Yakubu Princely AU - Acevedo-Arozena, Abraham AU - Adamopoulos, Iannis E. AU - Adeli, Khosrow AU - Adolph, Timon E. AU - Adornetto, Annagrazia AU - Aflaki, Elma AU - Agam, Galila AU - Agarwal, Anupam AU - Aggarwal, Bharat B. AU - Agnello, Maria AU - Agostinis, Patrizia AU - Agrewala, Javed N. AU - Agrotis, Alexander AU - Aguilar, Patricia V. AU - Ahmad, S. Tariq AU - Ahmed, Zubair M. AU - Ahumada-Castro, Ulises AU - Aits, Sonja AU - Aizawa, Shu AU - Akkoc, Yunus AU - Akoumianaki, Tonia AU - Akpinar, Hafize Aysin AU - Al-Abd, Ahmed M. AU - Al-Akra, Lina AU - Al-Gharaibeh, Abeer AU - Alaoui-Jamali, Moulay A. AU - Alberti, Simon AU - Alcocer-Gómez, Elísabet AU - Alessandri, Cristiano AU - Ali, Muhammad AU - Alim Al-Bari, M. Abdul AU - Aliwaini, Saeb AU - Alizadeh, Javad AU - Almacellas, Eugènia AU - Almasan, Alexandru AU - Alonso, Alicia AU - Alonso, Guillermo D. AU - Altan-Bonnet, Nihal AU - Altieri, Dario C. AU - Álvarez, Élida M.C. AU - Alves, Sara AU - Alves Da Costa, Cristine AU - Alzaharna, Mazen M. AU - Amadio, Marialaura AU - Amantini, Consuelo AU - Amaral, Cristina AU - Ambrosio, Susanna AU - Amer, Amal O. AU - Ammanathan, Veena AU - An, Zhenyi AU - Andersen, Stig U. AU - Andrabi, Shaida A. AU - Andrade-Silva, Magaiver AU - Andres, Allen M. AU - Angelini, Sabrina AU - Ann, David AU - Anozie, Uche C. AU - Ansari, Mohammad Y. AU - Antas, Pedro AU - Antebi, Adam AU - Antón, Zuriñe AU - Anwar, Tahira AU - Apetoh, Lionel AU - Apostolova, Nadezda AU - Araki, Toshiyuki AU - Araki, Yasuhiro AU - Arasaki, Kohei AU - Araújo, Wagner L. AU - Araya, Jun AU - Arden, Catherine AU - Arévalo, Maria Angeles AU - Arguelles, Sandro AU - Arias, Esperanza AU - Arikkath, Jyothi AU - Arimoto, Hirokazu AU - Ariosa, Aileen R. AU - Armstrong-James, Darius AU - Arnauné-Pelloquin, Laetitia AU - Aroca, Angeles AU - Arroyo, Daniela S. AU - Arsov, Ivica AU - Artero, Rubén AU - Asaro, Dalia Maria Lucia AU - Aschner, Michael AU - Ashrafizadeh, Milad AU - Ashur-Fabian, Osnat AU - Atanasov, Atanas G. AU - Au, Alicia K. AU - Auberger, Patrick AU - Auner, Holger W. AU - Aurelian, Laure AU - Autelli, Riccardo AU - Avagliano, Laura AU - Ávalos, Yenniffer AU - Aveic, Sanja AU - Aveleira, Célia Alexandra AU - Avin-Wittenberg, Tamar AU - Aydin, Yucel AU - Ayton, Scott AU - Ayyadevara, Srinivas AU - Azzopardi, Maria AU - Baba, Misuzu AU - Backer, Jonathan M. AU - Backues, Steven K. AU - Bae, Dong Hun AU - Bae, Ok Nam AU - Bae, Soo Han AU - Baehrecke, Eric H. AU - Baek, Ahruem AU - Baek, Seung Hoon AU - Baek, Sung Hee AU - Bagetta, Giacinto AU - Bagniewska-Zadworna, Agnieszka AU - Bai, Hua AU - Bai, Jie AU - Bai, Xiyuan AU - Bai, Yidong AU - Bairagi, Nandadulal AU - Baksi, Shounak AU - Balbi, Teresa AU - Baldari, Cosima T. AU - Balduini, Walter AU - Ballabio, Andrea AU - Ballester, Maria AU - Balazadeh, Salma AU - Balzan, Rena AU - Bandopadhyay, Rina AU - Banerjee, Sreeparna AU - Banerjee, Sulagna AU - Bánréti, Ágnes AU - Bao, Yan AU - Baptista, Mauricio S. AU - Baracca, Alessandra AU - Barbati, Cristiana AU - Bargiela, Ariadna AU - Barilà, Daniela AU - Barlow, Peter G. AU - Barmada, Sami J. AU - Barreiro, Esther AU - Barreto, George E. AU - Bartek, Jiri AU - Bartel, Bonnie AU - Bartolome, Alberto AU - Barve, Gaurav R. AU - Basagoudanavar, Suresh H. AU - Bassham, Diane C. AU - Bast, Robert C. AU - Basu, Alakananda AU - Batoko, Henri AU - Batten, Isabella AU - Baulieu, Etienne E. AU - Baumgarner, Bradley L. AU - Bayry, Jagadeesh AU - Beale, Rupert AU - Beau, Isabelle AU - Beaumatin, Florian AU - Bechara, Luiz R.G. AU - Beck, George R. AU - Beers, Michael F. AU - Begun, Jakob AU - Behrends, Christian AU - Behrens, Georg M.N. AU - Bei, Roberto AU - Bejarano, Eloy AU - Bel, Shai AU - Behl, Christian AU - Belaid, Amine AU - Belgareh-Touzé, Naïma AU - Bellarosa, Cristina AU - Belleudi, Francesca AU - Belló Pérez, Melissa AU - Bello-Morales, Raquel AU - Beltran, Jackeline Soares De Oliveira AU - Beltran, Sebastián AU - Benbrook, Doris Mangiaracina AU - Bendorius, Mykolas AU - Benitez, Bruno A. AU - Benito-Cuesta, Irene AU - Bensalem, Julien AU - Berchtold, Martin W. AU - Berezowska, Sabina AU - Bergamaschi, Daniele AU - Bergami, Matteo AU - Bergmann, Andreas AU - Berliocchi, Laura AU - Berlioz-Torrent, Clarisse AU - Bernard, Amélie AU - Berthoux, Lionel AU - Besirli, Cagri G. AU - Besteiro, Sebastien AU - Betin, Virginie M. AU - Beyaert, Rudi AU - Bezbradica, Jelena S. AU - Bhaskar, Kiran AU - Bhatia-Kissova, Ingrid AU - Bhattacharya, Resham AU - Bhattacharya, Sujoy AU - Bhattacharyya, Shalmoli AU - Bhuiyan, Md Shenuarin AU - Bhutia, Sujit Kumar AU - Bi, Lanrong AU - Bi, Xiaolin AU - Biden, Trevor J. AU - Bijian, Krikor AU - Billes, Viktor A. AU - Binart, Nadine AU - Bincoletto, Claudia AU - Birgisdottir, Asa B. AU - Bjorkoy, Geir AU - Blanco, Gonzalo AU - Blas-Garcia, Ana AU - Blasiak, Janusz AU - Blomgran, Robert AU - Blomgren, Klas AU - Blum, Janice S. AU - Boada-Romero, Emilio AU - Boban, Mirta AU - Boesze-Battaglia, Kathleen AU - Boeuf, Philippe AU - Boland, Barry AU - Bomont, Pascale AU - Bonaldo, Paolo AU - Bonam, Srinivasa Reddy AU - Bonfili, Laura AU - Bonifacino, Juan S. AU - Boone, Brian A. AU - Bootman, Martin D. AU - Bordi, Matteo AU - Borner, Christoph AU - Bornhauser, Beat C. AU - Borthakur, Gautam AU - Bosch, Jürgen AU - Bose, Santanu AU - Botana, Luis M. AU - Botas, Juan AU - Boulanger, Chantal M. AU - Boulton, Michael E. AU - Bourdenx, Mathieu AU - Bourgeois, Benjamin AU - Bourke, Nollaig M. AU - Bousquet, Guilhem AU - Boya, Patricia AU - Bozhkov, Peter V. AU - Bozi, Luiz H.M. AU - Bozkurt, Tolga O. AU - Brackney, Doug E. AU - Brandts, Christian H. AU - Braun, Ralf J. AU - Braus, Gerhard H. AU - Bravo-Sagua, Roberto AU - Bravo-San Pedro, José M. AU - Brest, Patrick AU - Bringer, Marie Agnès AU - Briones-Herrera, Alfredo AU - Broaddus, V. Courtney AU - Brodersen, Peter AU - Brodsky, Jeffrey L. AU - Brody, Steven L. AU - Bronson, Paola G. AU - Bronstein, Jeff M. AU - Brown, Carolyn N. AU - Brown, Rhoderick E. AU - Brum, Patricia C. AU - Brumell, John H. AU - Brunetti-Pierri, Nicola AU - Bruno, Daniele AU - Bryson-Richardson, Robert J. AU - Bucci, Cecilia AU - Buchrieser, Carmen AU - Bueno, Marta AU - Buitrago-Molina, Laura Elisa AU - Buraschi, Simone AU - Buch, Shilpa AU - Buchan, J. Ross AU - Buckingham, Erin M. AU - Budak, Hikmet AU - Budini, Mauricio AU - Bultynck, Geert AU - Burada, Florin AU - Burgoyne, Joseph R. AU - Burón, M. Isabel AU - Bustos, Victor AU - Büttner, Sabrina AU - Butturini, Elena AU - Byrd, Aaron AU - Cabas, Isabel AU - Cabrera-Benitez, Sandra AU - Cadwell, Ken AU - Cai, Jingjing AU - Cai, Lu AU - Cai, Qian AU - Cairó, Montserrat AU - Calbet, Jose A. AU - Caldwell, Guy A. AU - Caldwell, Kim A. AU - Call, Jarrod A. AU - Calvani, Riccardo AU - Calvo, Ana C. AU - Calvo-Rubio Barrera, Miguel AU - Camara, Niels O.S. AU - Camonis, Jacques H. AU - Camougrand, Nadine AU - Campanella, Michelangelo AU - Campbell, Edward M. AU - Campbell-Valois, François Xavier AU - Campello, Silvia AU - Campesi, Ilaria AU - Campos, Juliane C. AU - Camuzard, Olivier AU - Cancino, Jorge AU - Candido De Almeida, Danilo AU - Canesi, Laura AU - Caniggia, Isabella AU - Canonico, Barbara AU - Cantí, Carles AU - Cao, Bin AU - Caraglia, Michele AU - Caramés, Beatriz AU - Carchman, Evie H. AU - Cardenal-Muñoz, Elena AU - Cardenas, Cesar AU - Cardenas, Luis AU - Cardoso, Sandra M. AU - Carew, Jennifer S. AU - Carle, Georges F. AU - Carleton, Gillian AU - Carloni, Silvia AU - Carmona-Gutierrez, Didac AU - Carneiro, Leticia A. AU - Carnevali, Oliana AU - Carosi, Julian M. AU - Carra, Serena AU - Carrier, Alice AU - Carrier, Lucie AU - Carroll, Bernadette AU - Carter, A. Brent AU - Carvalho, Andreia Neves AU - Casanova, Magali AU - Casas, Caty AU - Casas, Josefina AU - Cassioli, Chiara AU - Castillo, Eliseo F. AU - Castillo, Karen AU - Castillo-Lluva, Sonia AU - Castoldi, Francesca AU - Castori, Marco AU - Castro, Ariel F. AU - Castro-Caldas, Margarida AU - Castro-Hernandez, Javier AU - Castro-Obregon, Susana AU - Catz, Sergio D. AU - Cavadas, Claudia AU - Cavaliere, Federica AU - Cavallini, Gabriella AU - Cavinato, Maria AU - Cayuela, Maria L. AU - Cebollada Rica, Paula AU - Cecarini, Valentina AU - Cecconi, Francesco AU - Cechowska-Pasko, Marzanna AU - Cenci, Simone AU - Ceperuelo-Mallafré, Victòria AU - Cerqueira, João J. AU - Cerutti, Janete M. AU - Cervia, Davide AU - Cetintas, Vildan Bozok AU - Cetrullo, Silvia AU - Chae, Han Jung AU - Chagin, Andrei S. AU - Chai, Chee Yin AU - Chakrabarti, Gopal AU - Chakrabarti, Oishee AU - Chakraborty, Tapas AU - Chakraborty, Trinad AU - Chami, Mounia AU - Chamilos, Georgios AU - Chan, David W. AU - Chan, Edmond Y.W. AU - Chan, Edward D. AU - Chan, H. Y.Edwin AU - Chan, Helen H. AU - Chan, Hung AU - Chan, Matthew T.V. AU - Chan, Yau Sang AU - Chandra, Partha K. AU - Chang, Chih Peng AU - Chang, Chunmei AU - Chang, Hao Chun AU - Chang, Kai AU - Chao, Jie AU - Chapman, Tracey AU - Charlet-Berguerand, Nicolas AU - Chatterjee, Samrat AU - Chaube, Shail K. AU - Chaudhary, Anu AU - Chauhan, Santosh AU - Chaum, Edward AU - Checler, Frédéric AU - Cheetham, Michael E. AU - Chen, Chang Shi AU - Chen, Guang Chao AU - Chen, Jian Fu AU - Chen, Liam L. AU - Chen, Leilei AU - Chen, Lin AU - Chen, Mingliang AU - Chen, Mu Kuan AU - Chen, Ning AU - Chen, Quan AU - Chen, Ruey Hwa AU - Chen, Shi AU - Chen, Wei AU - Chen, Weiqiang AU - Chen, Xin Ming AU - Chen, Xiong Wen AU - Chen, Xu AU - Chen, Yan AU - Chen, Ye Guang AU - Chen, Yingyu AU - Chen, Yongqiang AU - Chen, Yu Jen AU - Chen, Yue Qin AU - Chen, Zhefan Stephen AU - Chen, Zhi AU - Chen, Zhi Hua AU - Chen, Zhijian J. AU - Chen, Zhixiang AU - Cheng, Hanhua AU - Cheng, Jun AU - Cheng, Shi Yuan AU - Cheng, Wei AU - Cheng, Xiaodong AU - Cheng, Xiu Tang AU - Cheng, Yiyun AU - Cheng, Zhiyong AU - Chen, Zhong AU - Cheong, Heesun AU - Cheong, Jit Kong AU - Chernyak, Boris V. AU - Cherry, Sara AU - Cheung, Chi Fai Randy AU - Cheung, Chun Hei Antonio AU - Cheung, King Ho AU - Chevet, Eric AU - Chi, Richard J. AU - Chiang, Alan Kwok Shing AU - Chiaradonna, Ferdinando AU - Chiarelli, Roberto AU - Chiariello, Mario AU - Chica, Nathalia AU - Chiocca, Susanna AU - Chiong, Mario AU - Chiou, Shih Hwa AU - Chiramel, Abhilash I. AU - Chiurchiù, Valerio AU - Cho, Dong Hyung AU - Choe, Seong Kyu AU - Choi, Augustine M.K. AU - Choi, Mary E. AU - Choudhury, Kamalika Roy AU - Chow, Norman S. AU - Chu, Charleen T. AU - Chua, Jason P. AU - Chua, John Jia En AU - Chung, Hyewon AU - Chung, Kin Pan AU - Chung, Seockhoon AU - Chung, So Hyang AU - Chung, Yuen Li AU - Cianfanelli, Valentina AU - Ciechomska, Iwona A. AU - Cifuentes, Mariana AU - Cinque, Laura AU - Cirak, Sebahattin AU - Cirone, Mara AU - Clague, Michael J. AU - Clarke, Robert AU - Clementi, Emilio AU - Coccia, Eliana M. AU - Codogno, Patrice AU - Cohen, Ehud AU - Cohen, Mickael M. AU - Colasanti, Tania AU - Colasuonno, Fiorella AU - Colbert, Robert A. AU - Colell, Anna AU - Čolić, Miodrag AU - Coll, Nuria S. AU - Collins, Mark O. AU - Colombo, María I. AU - Colón-Ramos, Daniel A. AU - Combaret, Lydie AU - Comincini, Sergio AU - Cominetti, Márcia R. AU - Consiglio, Antonella AU - Conte, Andrea AU - Conti, Fabrizio AU - Contu, Viorica Raluca AU - Cookson, Mark R. AU - Coombs, Kevin M. AU - Coppens, Isabelle AU - Corasaniti, Maria Tiziana AU - Corkery, Dale P. AU - Cordes, Nils AU - Cortese, Katia AU - Costa, Maria Do Carmo AU - Costantino, Sarah AU - Costelli, Paola AU - Coto-Montes, Ana AU - Crack, Peter J. AU - Crespo, Jose L. AU - Criollo, Alfredo AU - Crippa, Valeria AU - Cristofani, Riccardo AU - Csizmadia, Tamas AU - Cuadrado, Antonio AU - Cui, Bing AU - Cui, Jun AU - Cui, Yixian AU - Cui, Yong AU - Culetto, Emmanuel AU - Cumino, Andrea C. AU - Cybulsky, Andrey V. AU - Czaja, Mark J. AU - Czuczwar, Stanislaw J. AU - D’Adamo, Stefania AU - D’Amelio, Marcello AU - D’Arcangelo, Daniela AU - D’Lugos, Andrew C. AU - D’Orazi, Gabriella AU - Da Silva, James A. AU - Dafsari, Hormos Salimi AU - Dagda, Ruben K. AU - Dagdas, Yasin AU - Daglia, Maria AU - Dai, Xiaoxia AU - Dai, Yun AU - Dai, Yuyuan AU - Dal Col, Jessica AU - Dalhaimer, Paul AU - Dalla Valle, Luisa AU - Dallenga, Tobias AU - Dalmasso, Guillaume AU - Damme, Markus AU - Dando, Ilaria AU - Dantuma, Nico P. AU - Darling, April L. AU - Das, Hiranmoy AU - Dasarathy, Srinivasan AU - Dasari, Santosh K. AU - Dash, Srikanta AU - Daumke, Oliver AU - Dauphinee, Adrian N. AU - Davies, Jeffrey S. AU - Dávila, Valeria A. AU - Davis, Roger J. AU - Davis, Tanja AU - Dayalan Naidu, Sharadha AU - De Amicis, Francesca AU - De Bosscher, Karolien AU - De Felice, Francesca AU - De Franceschi, Lucia AU - De Leonibus, Chiara AU - De Mattos Barbosa, Mayara G. AU - De Meyer, Guido R.Y. AU - De Milito, Angelo AU - De Nunzio, Cosimo AU - De Palma, Clara AU - De Santi, Mauro AU - De Virgilio, Claudio AU - De Zio, Daniela AU - Debnath, Jayanta AU - Debosch, Brian J. AU - Decuypere, Jean Paul AU - Deehan, Mark A. AU - Deflorian, Gianluca AU - Degregori, James AU - Dehay, Benjamin AU - Del Rio, Gabriel AU - Delaney, Joe R. AU - Delbridge, Lea M.D. AU - Delorme-Axford, Elizabeth AU - Delpino, M. Victoria AU - Demarchi, Francesca AU - Dembitz, Vilma AU - Demers, Nicholas D. AU - Deng, Hongbin AU - Deng, Zhiqiang AU - Dengjel, Joern AU - Dent, Paul AU - Denton, Donna AU - Depamphilis, Melvin L. AU - Der, Channing J. AU - Deretic, Vojo AU - Descoteaux, Albert AU - Devis, Laura AU - Devkota, Sushil AU - Devuyst, Olivier AU - Dewson, Grant AU - Dharmasivam, Mahendiran AU - Dhiman, Rohan AU - Di Bernardo, Diego AU - Di Cristina, Manlio AU - Di Domenico, Fabio AU - Di Fazio, Pietro AU - Di Fonzo, Alessio AU - Di Guardo, Giovanni AU - Di Guglielmo, Gianni M. AU - Di Leo, Luca AU - Di Malta, Chiara AU - Di Nardo, Alessia AU - Di Rienzo, Martina AU - Di Sano, Federica AU - Diallinas, George AU - Diao, Jiajie AU - Diaz-Araya, Guillermo AU - Díaz-Laviada, Inés AU - Dickinson, Jared M. AU - Diederich, Marc AU - Dieudé, Mélanie AU - Dikic, Ivan AU - Ding, Shiping AU - Ding, Wen Xing AU - Dini, Luciana AU - Dinić, Jelena AU - Dinic, Miroslav AU - Dinkova-Kostova, Albena T. AU - Dionne, Marc S. AU - Distler, Jörg H.W. AU - Diwan, Abhinav AU - Dixon, Ian M.C. AU - Djavaheri-Mergny, Mojgan AU - Dobrinski, Ina AU - Dobrovinskaya, Oxana AU - Dobrowolski, Radek AU - Dobson, Renwick C.J. AU - Đokić, Jelena AU - Dokmeci Emre, Serap AU - Donadelli, Massimo AU - Dong, Bo AU - Dong, Xiaonan AU - Dong, Zhiwu AU - Dorn, Gerald W. AU - Dotsch, Volker AU - Dou, Huan AU - Dou, Juan AU - Dowaidar, Moataz AU - Dridi, Sami AU - Drucker, Liat AU - Du, Ailian AU - Du, Caigan AU - Du, Guangwei AU - Du, Hai Ning AU - Du, Li Lin AU - Du Toit, André AU - Duan, Shao Bin AU - Duan, Xiaoqiong AU - Duarte, Sónia P. AU - Dubrovska, Anna AU - Dunlop, Elaine A. AU - Dupont, Nicolas AU - Durán, Raúl V. AU - Dwarakanath, Bilikere S. AU - Dyshlovoy, Sergey A. AU - Ebrahimi-Fakhari, Darius AU - Eckhart, Leopold AU - Edelstein, Charles L. AU - Efferth, Thomas AU - Eftekharpour, Eftekhar AU - Eichinger, Ludwig AU - Eid, Nabil AU - Eisenberg, Tobias AU - Eissa, N. Tony AU - Eissa, Sanaa AU - Ejarque, Miriam AU - El Andaloussi, Abdeljabar AU - El-Hage, Nazira AU - El-Naggar, Shahenda AU - Eleuteri, Anna Maria AU - El-Shafey, Eman S. AU - Elgendy, Mohamed AU - Eliopoulos, Aristides G. AU - Elizalde, María M. AU - Elks, Philip M. AU - Elsasser, Hans Peter AU - Elsherbiny, Eslam S. AU - Emerling, Brooke M. AU - Emre, N. C.Tolga AU - Eng, Christina H. AU - Engedal, Nikolai AU - Engelbrecht, Anna Mart AU - Engelsen, Agnete S.T. AU - Enserink, Jorrit M. AU - Escalante, Ricardo AU - Esclatine, Audrey AU - Escobar-Henriques, Mafalda AU - Eskelinen, Eeva Liisa AU - Espert, Lucile AU - Eusebio, Makandjou Ola AU - Fabrias, Gemma AU - Fabrizi, Cinzia AU - Facchiano, Antonio AU - Facchiano, Francesco AU - Fadeel, Bengt AU - Fader, Claudio AU - Faesen, Alex C. AU - Fairlie, W. Douglas AU - Falcó, Alberto AU - Falkenburger, Bjorn H. AU - Fan, Daping AU - Fan, Jie AU - Fan, Yanbo AU - Fang, Evandro F. AU - Fang, Yanshan AU - Fang, Yognqi AU - Fanto, Manolis AU - Farfel-Becker, Tamar AU - Faure, Mathias AU - Fazeli, Gholamreza AU - Fedele, Anthony O. AU - Feldman, Arthur M. AU - Feng, Du AU - Feng, Jiachun AU - Feng, Lifeng AU - Feng, Yibin AU - Feng, Yuchen AU - Feng, Wei AU - Fenz Araujo, Thais AU - Ferguson, Thomas A. AU - Fernández, Álvaro F. AU - Fernandez-Checa, Jose C. AU - Fernández-Veledo, Sonia AU - Fernie, Alisdair R. AU - Ferrante, Anthony W. AU - Ferraresi, Alessandra AU - Ferrari, Merari F. AU - Ferreira, Julio C.B. AU - Ferro-Novick, Susan AU - Figueras, Antonio AU - Filadi, Riccardo AU - Filigheddu, Nicoletta AU - Filippi-Chiela, Eduardo AU - Filomeni, Giuseppe AU - Fimia, Gian Maria AU - Fineschi, Vittorio AU - Finetti, Francesca AU - Finkbeiner, Steven AU - Fisher, Edward A. AU - Fisher, Paul B. AU - Flamigni, Flavio AU - Fliesler, Steven J. AU - Flo, Trude H. AU - Florance, Ida AU - Florey, Oliver AU - Florio, Tullio AU - Fodor, Erika AU - Follo, Carlo AU - Fon, Edward A. AU - Forlino, Antonella AU - Fornai, Francesco AU - Fortini, Paola AU - Fracassi, Anna AU - Fraldi, Alessandro AU - Franco, Brunella AU - Franco, Rodrigo AU - Franconi, Flavia AU - Frankel, Lisa B. AU - Friedman, Scott L. AU - Fröhlich, Leopold F. AU - Frühbeck, Gema AU - Fuentes, Jose M. AU - Fujiki, Yukio AU - Fujita, Naonobu AU - Fujiwara, Yuuki AU - Fukuda, Mitsunori AU - Fulda, Simone AU - Furic, Luc AU - Furuya, Norihiko AU - Fusco, Carmela AU - Gack, Michaela U. AU - Gaffke, Lidia AU - Galadari, Sehamuddin AU - Galasso, Alessia AU - Galindo, Maria F. AU - Gallolu Kankanamalage, Sachith AU - Galluzzi, Lorenzo AU - Galy, Vincent AU - Gammoh, Noor AU - Gan, Boyi AU - Ganley, Ian G. AU - Gao, Feng AU - Gao, Hui AU - Gao, Minghui AU - Gao, Ping AU - Gao, Shou Jiang AU - Gao, Wentao AU - Gao, Xiaobo AU - Garcera, Ana AU - Garcia, Maria Noé AU - Garcia, Verónica E. AU - García-Del Portillo, Francisco AU - Garcia-Escudero, Vega AU - Garcia-Garcia, Aracely AU - Garcia-Macia, Marina AU - García-Moreno, Diana AU - Garcia-Ruiz, Carmen AU - García-Sanz, Patricia AU - Garg, Abhishek D. AU - Gargini, Ricardo AU - Garofalo, Tina AU - Garry, Robert F. AU - Gassen, Nils C. AU - Gatica, Damian AU - Ge, Liang AU - Ge, Wanzhong AU - Geiss-Friedlander, Ruth AU - Gelfi, Cecilia AU - Genschik, Pascal AU - Gentle, Ian E. AU - Gerbino, Valeria AU - Gerhardt, Christoph AU - Germain, Kyla AU - Germain, Marc AU - Gewirtz, David A. AU - Ghasemipour Afshar, Elham AU - Ghavami, Saeid AU - Ghigo, Alessandra AU - Ghosh, Manosij AU - Giamas, Georgios AU - Giampietri, Claudia AU - Giatromanolaki, Alexandra AU - Gibson, Gary E. AU - Gibson, Spencer B. AU - Ginet, Vanessa AU - Giniger, Edward AU - Giorgi, Carlotta AU - Girao, Henrique AU - Girardin, Stephen E. AU - Giridharan, Mridhula AU - Giuliano, Sandy AU - Giulivi, Cecilia AU - Giuriato, Sylvie AU - Giustiniani, Julien AU - Gluschko, Alexander AU - Goder, Veit AU - Goginashvili, Alexander AU - Golab, Jakub AU - Goldstone, David C. AU - Golebiewska, Anna AU - Gomes, Luciana R. AU - Gomez, Rodrigo AU - Gómez-Sánchez, Rubén AU - Gomez-Puerto, Maria Catalina AU - Gomez-Sintes, Raquel AU - Gong, Qingqiu AU - Goni, Felix M. AU - González-Gallego, Javier AU - Gonzalez-Hernandez, Tomas AU - Gonzalez-Polo, Rosa A. AU - Gonzalez-Reyes, Jose A. AU - González-Rodríguez, Patricia AU - Goping, Ing Swie AU - Gorbatyuk, Marina S. AU - Gorbunov, Nikolai V. AU - Görgülü, Kıvanç AU - Gorojod, Roxana M. AU - Gorski, Sharon M. AU - Goruppi, Sandro AU - Gotor, Cecilia AU - Gottlieb, Roberta A. AU - Gozes, Illana AU - Gozuacik, Devrim AU - Graef, Martin AU - Gräler, Markus H. AU - Granatiero, Veronica AU - Grasso, Daniel AU - Gray, Joshua P. AU - Green, Douglas R. AU - Greenhough, Alexander AU - Gregory, Stephen L. AU - Griffin, Edward F. AU - Grinstaff, Mark W. AU - Gros, Frederic AU - Grose, Charles AU - Gross, Angelina S. AU - Gruber, Florian AU - Grumati, Paolo AU - Grune, Tilman AU - Gu, Xueyan AU - Guan, Jun Lin AU - Guardia, Carlos M. AU - Guda, Kishore AU - Guerra, Flora AU - Guerri, Consuelo AU - Guha, Prasun AU - Guillén, Carlos AU - Gujar, Shashi AU - Gukovskaya, Anna AU - Gukovsky, Ilya AU - Gunst, Jan AU - Günther, Andreas AU - Guntur, Anyonya R. AU - Guo, Chuanyong AU - Guo, Chun AU - Guo, Hongqing AU - Guo, Lian Wang AU - Guo, Ming AU - Gupta, Pawan AU - Gupta, Shashi Kumar AU - Gupta, Swapnil AU - Gupta, Veer Bala AU - Gupta, Vivek AU - Gustafsson, Asa B. AU - Gutterman, David D. AU - H.B, Ranjitha AU - Haapasalo, Annakaisa AU - Haber, James E. AU - Hać, Aleksandra AU - Hadano, Shinji AU - Hafrén, Anders J. AU - Haidar, Mansour AU - Hall, Belinda S. AU - Halldén, Gunnel AU - Hamacher-Brady, Anne AU - Hamann, Andrea AU - Hamasaki, Maho AU - Han, Weidong AU - Hansen, Malene AU - Hanson, Phyllis I. . AU - Hao, Zijian AU - Harada, Masaru AU - Harhaji-Trajkovic, Ljubica AU - Hariharan, Nirmala AU - Haroon, Nigil AU - Harris, James AU - Hasegawa, Takafumi AU - Hasima Nagoor, Noor AU - Haspel, Jeffrey A. AU - Haucke, Volker AU - Hawkins, Wayne D. AU - Hay, Bruce A. AU - Haynes, Cole M. AU - Hayrabedyan, Soren B. AU - Hays, Thomas S. AU - He, Congcong AU - He, Qin AU - He, Rong Rong AU - He, You Wen AU - He, Yu Ying AU - Heakal, Yasser AU - Heberle, Alexander M. AU - Hejtmancik, J. Fielding AU - Helgason, Gudmundur Vignir AU - Henkel, Vanessa AU - Herb, Marc AU - Hergovich, Alexander AU - Herman-Antosiewicz, Anna AU - Hernández, Agustín AU - Hernandez, Carlos AU - Hernandez-Diaz, Sergio AU - Hernandez-Gea, Virginia AU - Herpin, Amaury AU - Herreros, Judit AU - Hervás, Javier H. AU - Hesselson, Daniel AU - Hetz, Claudio AU - Heussler, Volker T. AU - Higuchi, Yujiro AU - Hilfiker, Sabine AU - Hill, Joseph A. AU - Hlavacek, William S. AU - Ho, Emmanuel A. AU - Ho, Idy H.T. AU - Ho, Philip Wing Lok AU - Ho, Shu Leong AU - Ho, Wan Yun AU - Hobbs, G. Aaron AU - Hochstrasser, Mark AU - Hoet, Peter H.M. AU - Hofius, Daniel AU - Hofman, Paul AU - Höhn, Annika AU - Holmberg, Carina I. AU - Hombrebueno, Jose R. AU - Yi-Ren Hong, Chang Won Hong AU - Hooper, Lora V. AU - Hoppe, Thorsten AU - Horos, Rastislav AU - Hoshida, Yujin AU - Hsin, I. Lun AU - Hsu, Hsin Yun AU - Hu, Bing AU - Hu, Dong AU - Hu, Li Fang AU - Hu, Ming Chang AU - Hu, Ronggui AU - Hu, Wei AU - Hu, Yu Chen AU - Hu, Zhuo Wei AU - Hua, Fang AU - Hua, Jinlian AU - Hua, Yingqi AU - Huan, Chongmin AU - Huang, Canhua AU - Huang, Chuanshu AU - Huang, Chuanxin AU - Huang, Chunling AU - Huang, Haishan AU - Huang, Kun AU - Huang, Michael L.H. AU - Huang, Rui AU - Huang, Shan AU - Huang, Tianzhi AU - Huang, Xing AU - Huang, Yuxiang Jack AU - Huber, Tobias B. AU - Hubert, Virginie AU - Hubner, Christian A. AU - Hughes, Stephanie M. AU - Hughes, William E. AU - Humbert, Magali AU - Hummer, Gerhard AU - Hurley, James H. AU - Hussain, Sabah AU - Hussain, Salik AU - Hussey, Patrick J. AU - Hutabarat, Martina AU - Hwang, Hui Yun AU - Hwang, Seungmin AU - Ieni, Antonio AU - Ikeda, Fumiyo AU - Imagawa, Yusuke AU - Imai, Yuzuru AU - Imbriano, Carol AU - Imoto, Masaya AU - Inman, Denise M. AU - Inoki, Ken AU - Iovanna, Juan AU - Iozzo, Renato V. AU - Ippolito, Giuseppe AU - Irazoqui, Javier E. AU - Iribarren, Pablo AU - Ishaq, Mohd AU - Ishikawa, Makoto AU - Ishimwe, Nestor AU - Isidoro, Ciro AU - Ismail, Nahed AU - Issazadeh-Navikas, Shohreh AU - Itakura, Eisuke AU - Ito, Daisuke AU - Ivankovic, Davor AU - Ivanova, Saška AU - Iyer, Anand Krishnan V. AU - Izquierdo, José M. AU - Izumi, Masanori AU - Jäättelä, Marja AU - Jabir, Majid Sakhi AU - Jackson, William T. AU - Jacobo-Herrera, Nadia AU - Jacomin, Anne Claire AU - Jacquin, Elise AU - Jadiya, Pooja AU - Jaeschke, Hartmut AU - Jagannath, Chinnaswamy AU - Jakobi, Arjen J. AU - Jakobsson, Johan AU - Janji, Bassam AU - Jansen-Dürr, Pidder AU - Jansson, Patric J. AU - Jantsch, Jonathan AU - Januszewski, Sławomir AU - Jassey, Alagie AU - Jean, Steve AU - Jeltsch-David, Hélène AU - Jendelova, Pavla AU - Jenny, Andreas AU - Jensen, Thomas E. AU - Jessen, Niels AU - Jewell, Jenna L. AU - Ji, Jing AU - Jia, Lijun AU - Jia, Rui AU - Jiang, Liwen AU - Jiang, Qing AU - Jiang, Richeng AU - Jiang, Teng AU - Jiang, Xuejun AU - Jiang, Yu AU - Jimenez-Sanchez, Maria AU - Jin, Eun Jung AU - Jin, Fengyan AU - Jin, Hongchuan AU - Jin, Li AU - Jin, Luqi AU - Jin, Meiyan AU - Jin, Si AU - Jo, Eun Kyeong AU - Joffre, Carine AU - Johansen, Terje AU - Johnson, Gail V.W. AU - Johnston, Simon A. AU - Jokitalo, Eija AU - Jolly, Mohit Kumar AU - Joosten, Leo A.B. AU - Jordan, Joaquin AU - Joseph, Bertrand AU - Ju, Dianwen AU - Ju, Jeong Sun AU - Ju, Jingfang AU - Juárez, Esmeralda AU - Judith, Delphine AU - Juhász, Gábor AU - Jun, Youngsoo AU - Jung, Chang Hwa AU - Jung, Sung Chul AU - Jung, Yong Keun AU - Jungbluth, Heinz AU - Jungverdorben, Johannes AU - Just, Steffen AU - Kaarniranta, Kai AU - Kaasik, Allen AU - Kabuta, Tomohiro AU - Kaganovich, Daniel AU - Kahana, Alon AU - Kain, Renate AU - Kajimura, Shinjo AU - Kalamvoki, Maria AU - Kalia, Manjula AU - Kalinowski, Danuta S. AU - Kaludercic, Nina AU - Kalvari, Ioanna AU - Kaminska, Joanna AU - Kaminskyy, Vitaliy O. AU - Kanamori, Hiromitsu AU - Kanasaki, Keizo AU - Kang, Chanhee AU - Kang, Rui AU - Kang, Sang Sun AU - Kaniyappan, Senthilvelrajan AU - Kanki, Tomotake AU - Kanneganti, Thirumala Devi AU - Kanthasamy, Anumantha G. AU - Kanthasamy, Arthi AU - Kantorow, Marc AU - Kapuy, Orsolya AU - Karamouzis, Michalis V. AU - Karim, Md Razaul AU - Karmakar, Parimal AU - Katare, Rajesh G. AU - Kato, Masaru AU - Kaufmann, Stefan H.E. AU - Kauppinen, Anu AU - Kaushal, Gur P. AU - Kaushik, Susmita AU - Kawasaki, Kiyoshi AU - Kazan, Kemal AU - Ke, Po Yuan AU - Keating, Damien J. AU - Keber, Ursula AU - Kehrl, John H. AU - Keller, Kate E. AU - Keller, Christian W. AU - Kemper, Jongsook Kim AU - Kenific, Candia M. AU - Kepp, Oliver AU - Kermorgant, Stephanie AU - Kern, Andreas AU - Ketteler, Robin AU - Keulers, Tom G. AU - Khalfin, Boris AU - Khalil, Hany AU - Khambu, Bilon AU - Khan, Shahid Y. AU - Khandelwal, Vinoth Kumar Megraj AU - Khandia, Rekha AU - Kho, Widuri AU - Khobrekar, Noopur V. AU - Khuansuwan, Sataree AU - Khundadze, Mukhran AU - Killackey, Samuel A. AU - Kim, Dasol AU - Kim, Deok Ryong AU - Kim, Do Hyung AU - Kim, Dong Eun AU - Kim, Eun Young AU - Kim, Eun Kyoung AU - Kim, Hak Rim AU - Kim, Hee Sik AU - Hyung-Ryong Kim, Unknown AU - Kim, Jeong Hun AU - Kim, Jin Kyung AU - Kim, Jin Hoi AU - Kim, Joungmok AU - Kim, Ju Hwan AU - Kim, Keun Il AU - Kim, Peter K. AU - Kim, Seong Jun AU - Kimball, Scot R. AU - Kimchi, Adi AU - Kimmelman, Alec C. AU - Kimura, Tomonori AU - King, Matthew A. AU - Kinghorn, Kerri J. AU - Kinsey, Conan G. AU - Kirkin, Vladimir AU - Kirshenbaum, Lorrie A. AU - Kiselev, Sergey L. AU - Kishi, Shuji AU - Kitamoto, Katsuhiko AU - Kitaoka, Yasushi AU - Kitazato, Kaio AU - Kitsis, Richard N. AU - Kittler, Josef T. AU - Kjaerulff, Ole AU - Klein, Peter S. AU - Klopstock, Thomas AU - Klucken, Jochen AU - Knævelsrud, Helene AU - Knorr, Roland L. AU - Ko, Ben C.B. AU - Ko, Fred AU - Ko, Jiunn Liang AU - Kobayashi, Hotaka AU - Kobayashi, Satoru AU - Koch, Ina AU - Koch, Jan C. AU - Koenig, Ulrich AU - Kögel, Donat AU - Koh, Young Ho AU - Koike, Masato AU - Kohlwein, Sepp D. AU - Kocaturk, Nur M. AU - Komatsu, Masaaki AU - König, Jeannette AU - Kono, Toru AU - Kopp, Benjamin T. AU - Korcsmaros, Tamas AU - Korkmaz, Gözde AU - Korolchuk, Viktor I. AU - Korsnes, Mónica Suárez AU - Koskela, Ali AU - Kota, Janaiah AU - Kotake, Yaichiro AU - Kotler, Monica L. AU - Kou, Yanjun AU - Koukourakis, Michael I. AU - Koustas, Evangelos AU - Kovacs, Attila L. AU - Kovács, Tibor AU - Koya, Daisuke AU - Kozako, Tomohiro AU - Kraft, Claudine AU - Krainc, Dimitri AU - Krämer, Helmut AU - Krasnodembskaya, Anna D. AU - Kretz-Remy, Carole AU - Kroemer, Guido AU - Ktistakis, Nicholas T. AU - Kuchitsu, Kazuyuki AU - Kuenen, Sabine AU - Kuerschner, Lars AU - Kukar, Thomas AU - Kumar, Ajay AU - Kumar, Ashok AU - Kumar, Deepak AU - Kumar, Dhiraj AU - Kumar, Sharad AU - Kume, Shinji AU - Kumsta, Caroline AU - Kundu, Chanakya N. AU - Kundu, Mondira AU - Kunnumakkara, Ajaikumar B. AU - Kurgan, Lukasz AU - Kutateladze, Tatiana G. AU - Kutlu, Ozlem AU - Kwak, Seong Ae AU - Kwon, Ho Jeong AU - Kwon, Taeg Kyu AU - Kwon, Yong Tae AU - Kyrmizi, Irene AU - La Spada, Albert AU - Labonté, Patrick AU - Ladoire, Sylvain AU - Laface, Ilaria AU - Lafont, Frank AU - Lagace, Diane C. AU - Lahiri, Vikramjit AU - Lai, Zhibing AU - Laird, Angela S. AU - Lakkaraju, Aparna AU - Lamark, Trond AU - Lan, Sheng Hui AU - Landajuela, Ane AU - Lane, Darius J.R. AU - Lane, Jon D. AU - Lang, Charles H. AU - Lange, Carsten AU - Langel, Ülo AU - Langer, Rupert AU - Lapaquette, Pierre AU - Laporte, Jocelyn AU - Larusso, Nicholas F. AU - Lastres-Becker, Isabel AU - Lau, Wilson Chun Yu AU - Laurie, Gordon W. AU - Lavandero, Sergio AU - Law, Betty Yuen Kwan AU - Law, Helen Ka Wai AU - Layfield, Rob AU - Le, Weidong AU - Le Stunff, Herve AU - Leary, Alexandre Y. AU - Lebrun, Jean Jacques AU - Leck, Lionel Y.W. AU - Leduc-Gaudet, Jean Philippe AU - Lee, Changwook AU - Lee, Chung Pei AU - Lee, Da Hye AU - Lee, Edward B. AU - Lee, Erinna F. AU - Lee, Gyun Min AU - Lee, He Jin AU - Lee, Heung Kyu AU - Lee, Jae Man AU - Lee, Jason S. AU - Lee, Jin A. AU - Lee, Joo Yong AU - Lee, Jun Hee AU - Lee, Michael AU - Lee, Min Goo AU - Lee, Min Jae AU - Lee, Myung Shik AU - Lee, Sang Yoon AU - Lee, Seung Jae AU - Lee, Stella Y. AU - Lee, Sung Bae AU - Lee, Won Hee AU - Lee, Ying Ray AU - Lee, Yong Ho AU - Lee, Youngil AU - Lefebvre, Christophe AU - Legouis, Renaud AU - Lei, Yu L. AU - Lei, Yuchen AU - Leikin, Sergey AU - Leitinger, Gerd AU - Lemus, Leticia AU - Leng, Shuilong AU - Lenoir, Olivia AU - Lenz, Guido AU - Lenz, Heinz Josef AU - Lenzi, Paola AU - León, Yolanda AU - Leopoldino, Andréia M. AU - Leschczyk, Christoph AU - Leskelä, Stina AU - Letellier, Elisabeth AU - Leung, Chi Ting AU - Leung, Po Sing AU - Leventhal, Jeremy S. AU - Levine, Beth AU - Lewis, Patrick A. AU - Ley, Klaus AU - Li, Bin AU - Li, Da Qiang AU - Li, Jianming AU - Li, Jing AU - Li, Jiong AU - Li, Ke AU - Li, Liwu AU - Li, Mei AU - Li, Min AU - Li, Min AU - Li, Ming AU - Li, Mingchuan AU - Li, Pin Lan AU - Li, Ming Qing AU - Li, Qing AU - Li, Sheng AU - Li, Tiangang AU - Li, Wei AU - Li, Wenming AU - Li, Xue AU - Li, Yi Ping AU - Li, Yuan AU - Li, Zhiqiang AU - Li, Zhiyong AU - Li, Zhiyuan AU - Lian, Jiqin AU - Liang, Chengyu AU - Liang, Qiangrong AU - Liang, Weicheng AU - Liang, Yongheng AU - Liang, Yong Tian AU - Liao, Guanghong AU - Liao, Lujian AU - Liao, Mingzhi AU - Liao, Yung Feng AU - Librizzi, Mariangela AU - Lie, Pearl P.Y. AU - Lilly, Mary A. AU - Lim, Hyunjung J. AU - Lima, Thania R.R. AU - Limana, Federica AU - Lin, Chao AU - Lin, Chih Wen AU - Lin, Dar Shong AU - Lin, Fu Cheng AU - Lin, Jiandie D. AU - Lin, Kurt M. AU - Lin, Kwang Huei AU - Lin, Liang Tzung AU - Lin, Pei Hui AU - Lin, Qiong AU - Lin, Shaofeng AU - Lin, Su Ju AU - Lin, Wenyu AU - Lin, Xueying AU - Lin, Yao Xin AU - Lin, Yee Shin AU - Linden, Rafael AU - Lindner, Paula AU - Ling, Shuo Chien AU - Lingor, Paul AU - Linnemann, Amelia K. AU - Liou, Yih Cherng AU - Lipinski, Marta M. AU - Lipovšek, Saška AU - Lira, Vitor A. AU - Lisiak, Natalia AU - Liton, Paloma B. AU - Liu, Chao AU - Liu, Ching Hsuan AU - Liu, Chun Feng AU - Liu, Cui Hua AU - Liu, Fang AU - Liu, Hao AU - Liu, Hsiao Sheng AU - Liu, Hua Feng AU - Liu, Huifang AU - Liu, Jia AU - Liu, Jing AU - Liu, Julia AU - Liu, Leyuan AU - Liu, Longhua AU - Liu, Meilian AU - Liu, Qin AU - Liu, Wei AU - Liu, Wende AU - Liu, Xiao Hong AU - Liu, Xiaodong AU - Liu, Xingguo AU - Liu, Xu AU - Liu, Xuedong AU - Liu, Yanfen AU - Liu, Yang AU - Liu, Yang AU - Liu, Yueyang AU - Liu, Yule AU - Livingston, J. Andrew AU - Lizard, Gerard AU - Lizcano, Jose M. AU - Ljubojevic-Holzer, Senka AU - Lleonart, Matilde E. AU - Llobet-Navàs, David AU - Llorente, Alicia AU - Lo, Chih Hung AU - Lobato-Márquez, Damián AU - Long, Qi AU - Long, Yun Chau AU - Loos, Ben AU - Loos, Julia A. AU - López, Manuela G. AU - López-Doménech, Guillermo AU - López-Guerrero, José Antonio AU - López-Jiménez, Ana T. AU - López-Pérez, Óscar AU - López-Valero, Israel AU - Lorenowicz, Magdalena J. AU - Lorente, Mar AU - Lorincz, Peter AU - Lossi, Laura AU - Lotersztajn, Sophie AU - Lovat, Penny E. AU - Lovell, Jonathan F. AU - Lovy, Alenka AU - Lőw, Péter AU - Lu, Guang AU - Lu, Haocheng AU - Lu, Jia Hong AU - Lu, Jin Jian AU - Lu, Mengji AU - Lu, Shuyan AU - Luciani, Alessandro AU - Lucocq, John M. AU - Ludovico, Paula AU - Luftig, Micah A. AU - Luhr, Morten AU - Luis-Ravelo, Diego AU - Lum, Julian J. AU - Luna-Dulcey, Liany AU - Lund, Anders H. AU - Lund, Viktor K. AU - Lünemann, Jan D. AU - Lüningschrör, Patrick AU - Luo, Honglin AU - Luo, Rongcan AU - Luo, Shouqing AU - Luo, Zhi AU - Luparello, Claudio AU - Lüscher, Bernhard AU - Luu, Luan AU - Lyakhovich, Alex AU - Lyamzaev, Konstantin G. AU - Lystad, Alf Håkon AU - Lytvynchuk, Lyubomyr AU - Ma, Alvin C. AU - Ma, Changle AU - Ma, Mengxiao AU - Ma, Ning Fang AU - Ma, Quan Hong AU - Ma, Xinliang AU - Ma, Yueyun AU - Ma, Zhenyi AU - Macdougald, Ormond A. AU - Macian, Fernando AU - Macintosh, Gustavo C. AU - Mackeigan, Jeffrey P. AU - Macleod, Kay F. AU - Maday, Sandra AU - Madeo, Frank AU - Madesh, Muniswamy AU - Madl, Tobias AU - Madrigal-Matute, Julio AU - Maeda, Akiko AU - Maejima, Yasuhiro AU - Magarinos, Marta AU - Mahavadi, Poornima AU - Maiani, Emiliano AU - Maiese, Kenneth AU - Maiti, Panchanan AU - Maiuri, Maria Chiara AU - Majello, Barbara AU - Major, Michael B. AU - Makareeva, Elena AU - Malik, Fayaz AU - Mallilankaraman, Karthik AU - Malorni, Walter AU - Maloyan, Alina AU - Mammadova, Najiba AU - Man, Gene Chi Wai AU - Manai, Federico AU - Mancias, Joseph D. AU - Mandelkow, Eva Maria AU - Mandell, Michael A. AU - Manfredi, Angelo A. AU - Manjili, Masoud H. AU - Manjithaya, Ravi AU - Manque, Patricio AU - Manshian, Bella B. AU - Manzano, Raquel AU - Manzoni, Claudia AU - Mao, Kai AU - Marchese, Cinzia AU - Marchetti, Sandrine AU - Marconi, Anna Maria AU - Marcucci, Fabrizio AU - Mardente, Stefania AU - Mareninova, Olga A. AU - Margeta, Marta AU - Mari, Muriel AU - Marinelli, Sara AU - Marinelli, Oliviero AU - Mariño, Guillermo AU - Mariotto, Sofia AU - Marshall, Richard S. AU - Marten, Mark R. AU - Martens, Sascha AU - Martin, Alexandre P.J. AU - Martin, Katie R. AU - Martin, Sara AU - Martin, Shaun AU - Martín-Segura, Adrián AU - Martín-Acebes, Miguel A. AU - Martin-Burriel, Inmaculada AU - Martin-Rincon, Marcos AU - Martin-Sanz, Paloma AU - Martina, José A. AU - Martinet, Wim AU - Martinez, Aitor AU - Martinez, Ana AU - Martinez, Jennifer AU - Martinez Velazquez, Moises AU - Martinez-Lopez, Nuria AU - Martinez-Vicente, Marta AU - Martins, Daniel O. AU - Martins, Joilson O. AU - Martins, Waleska K. AU - Martins-Marques, Tania AU - Marzetti, Emanuele AU - Masaldan, Shashank AU - Masclaux-Daubresse, Celine AU - Mashek, Douglas G. AU - Massa, Valentina AU - Massieu, Lourdes AU - Masson, Glenn R. AU - Masuelli, Laura AU - Masyuk, Anatoliy I. AU - Masyuk, Tetyana V. AU - Matarrese, Paola AU - Matheu, Ander AU - Matoba, Satoaki AU - Matsuzaki, Sachiko AU - Mattar, Pamela AU - Matte, Alessandro AU - Mattoscio, Domenico AU - Mauriz, José L. AU - Mauthe, Mario AU - Mauvezin, Caroline AU - Maverakis, Emanual AU - Maycotte, Paola AU - Mayer, Johanna AU - Mazzoccoli, Gianluigi AU - Mazzoni, Cristina AU - Mazzulli, Joseph R. AU - Mccarty, Nami AU - Mcdonald, Christine AU - Mcgill, Mitchell R. AU - Mckenna, Sharon L. AU - Mclaughlin, Beth Ann AU - Mcloughlin, Fionn AU - Mcniven, Mark A. AU - Mcwilliams, Thomas G. AU - Mechta-Grigoriou, Fatima AU - Medeiros, Tania Catarina AU - Medina, Diego L. AU - Megeney, Lynn A. AU - Megyeri, Klara AU - Mehrpour, Maryam AU - Mehta, Jawahar L. AU - Meijer, Alfred J. AU - Meijer, Annemarie H. AU - Mejlvang, Jakob AU - Meléndez, Alicia AU - Melk, Annette AU - Memisoglu, Gonen AU - Mendes, Alexandrina F. AU - Meng, Delong AU - Meng, Fei AU - Meng, Tian AU - Menna-Barreto, Rubem AU - Menon, Manoj B. AU - Mercer, Carol AU - Mercier, Anne E. AU - Mergny, Jean Louis AU - Merighi, Adalberto AU - Merkley, Seth D. AU - Merla, Giuseppe AU - Meske, Volker AU - Mestre, Ana Cecilia AU - Metur, Shree Padma AU - Meyer, Christian AU - Meyer, Hemmo AU - Mi, Wenyi AU - Mialet-Perez, Jeanne AU - Miao, Junying AU - Micale, Lucia AU - Miki, Yasuo AU - Milan, Enrico AU - Milczarek, Małgorzata AU - Miller, Dana L. AU - Miller, Samuel I. AU - Miller, Silke AU - Millward, Steven W. AU - Milosevic, Ira AU - Minina, Elena A. AU - Mirzaei, Hamed AU - Mirzaei, Hamid Reza AU - Mirzaei, Mehdi AU - Mishra, Amit AU - Mishra, Nandita AU - Mishra, Paras Kumar AU - Misirkic Marjanovic, Maja AU - Misasi, Roberta AU - Misra, Amit AU - Misso, Gabriella AU - Mitchell, Claire AU - Mitou, Geraldine AU - Miura, Tetsuji AU - Miyamoto, Shigeki AU - Miyazaki, Makoto AU - Miyazaki, Mitsunori AU - Miyazaki, Taiga AU - Miyazawa, Keisuke AU - Mizushima, Noboru AU - Mogensen, Trine H. AU - Mograbi, Baharia AU - Mohammadinejad, Reza AU - Mohamud, Yasir AU - Mohanty, Abhishek AU - Mohapatra, Sipra AU - Möhlmann, Torsten AU - Mohmmed, Asif AU - Moles, Anna AU - Moley, Kelle H. AU - Molinari, Maurizio AU - Mollace, Vincenzo AU - Møller, Andreas Buch AU - Mollereau, Bertrand AU - Mollinedo, Faustino AU - Montagna, Costanza AU - Monteiro, Mervyn J. AU - Montella, Andrea AU - Montes, L. Ruth AU - Montico, Barbara AU - Mony, Vinod K. AU - Monzio Compagnoni, Giacomo AU - Moore, Michael N. AU - Moosavi, Mohammad A. AU - Mora, Ana L. AU - Mora, Marina AU - Morales-Alamo, David AU - Moratalla, Rosario AU - Moreira, Paula I. AU - Morelli, Elena AU - Moreno, Sandra AU - Moreno-Blas, Daniel AU - Moresi, Viviana AU - Morga, Benjamin AU - Morgan, Alwena H. AU - Morin, Fabrice AU - Morishita, Hideaki AU - Moritz, Orson L. AU - Moriyama, Mariko AU - Moriyasu, Yuji AU - Morleo, Manuela AU - Morselli, Eugenia AU - Moruno-Manchon, Jose F. AU - Moscat, Jorge AU - Mostowy, Serge AU - Motori, Elisa AU - Moura, Andrea Felinto AU - Moustaid-Moussa, Naima AU - Mrakovcic, Maria AU - Muciño-Hernández, Gabriel AU - Mukherjee, Anupam AU - Mukhopadhyay, Subhadip AU - Mulcahy Levy, Jean M. AU - Mulero, Victoriano AU - Muller, Sylviane AU - Münch, Christian AU - Munjal, Ashok AU - Munoz-Canoves, Pura AU - Muñoz-Galdeano, Teresa AU - Münz, Christian AU - Murakawa, Tomokazu AU - Muratori, Claudia AU - Murphy, Brona M. AU - Murphy, J. Patrick AU - Murthy, Aditya AU - Myöhänen, Timo T. AU - Mysorekar, Indira U. AU - Mytych, Jennifer AU - Nabavi, Seyed Mohammad AU - Nabissi, Massimo AU - Nagy, Péter AU - Nah, Jihoon AU - Nahimana, Aimable AU - Nakagawa, Ichiro AU - Nakamura, Ken AU - Nakatogawa, Hitoshi AU - Nandi, Shyam S. AU - Nanjundan, Meera AU - Nanni, Monica AU - Napolitano, Gennaro AU - Nardacci, Roberta AU - Narita, Masashi AU - Nassif, Melissa AU - Nathan, Ilana AU - Natsumeda, Manabu AU - Naude, Ryno J. AU - Naumann, Christin AU - Naveiras, Olaia AU - Navid, Fatemeh AU - Nawrocki, Steffan T. AU - Nazarko, Taras Y. AU - Nazio, Francesca AU - Negoita, Florentina AU - Neill, Thomas AU - Neisch, Amanda L. AU - Neri, Luca M. AU - Netea, Mihai G. AU - Neubert, Patrick AU - Neufeld, Thomas P. AU - Neumann, Dietbert AU - Neutzner, Albert AU - Newton, Phillip T. AU - Ney, Paul A. AU - Nezis, Ioannis P. AU - Ng, Charlene C.W. AU - Ng, Tzi Bun AU - Nguyen, Hang T.T. AU - Nguyen, Long T. AU - Ni, Hong Min AU - Ní Cheallaigh, Clíona AU - Ni, Zhenhong AU - Nicolao, M. Celeste AU - Nicoli, Francesco AU - Nieto-Diaz, Manuel AU - Nilsson, Per AU - Ning, Shunbin AU - Niranjan, Rituraj AU - Nishimune, Hiroshi AU - Niso-Santano, Mireia AU - Nixon, Ralph A. AU - Nobili, Annalisa AU - Nobrega, Clevio AU - Noda, Takeshi AU - Nogueira-Recalde, Uxía AU - Nolan, Trevor M. AU - Nombela, Ivan AU - Novak, Ivana AU - Novoa, Beatriz AU - Nozawa, Takashi AU - Nukina, Nobuyuki AU - Nussbaum-Krammer, Carmen AU - Nylandsted, Jesper AU - O’Donovan, Tracey R. AU - O’Leary, Seónadh M. AU - O’Rourke, Eyleen J. AU - O’Sullivan, Mary P. AU - O’Sullivan, Timothy E. AU - Oddo, Salvatore AU - Oehme, Ina AU - Ogawa, Michinaga AU - Ogier-Denis, Eric AU - Ogmundsdottir, Margret H. AU - Ogretmen, Besim AU - Oh, Goo Taeg AU - Oh, Seon Hee AU - Oh, Young J. AU - Ohama, Takashi AU - Ohashi, Yohei AU - Ohmuraya, Masaki AU - Oikonomou, Vasileios AU - Ojha, Rani AU - Okamoto, Koji AU - Okazawa, Hitoshi AU - Oku, Masahide AU - Oliván, Sara AU - Oliveira, Jorge M.A. AU - Ollmann, Michael AU - Olzmann, James A. AU - Omari, Shakib AU - Omary, M. Bishr AU - Önal, Gizem AU - Ondrej, Martin AU - Ong, Sang Bing AU - Ong, Sang Ging AU - Onnis, Anna AU - Orellana, Juan A. AU - Orellana-Muñoz, Sara AU - Ortega-Villaizan, Maria Del Mar AU - Ortiz-Gonzalez, Xilma R. AU - Ortona, Elena AU - Osiewacz, Heinz D. AU - Osman, Abdel Hamid K. AU - Osta, Rosario AU - Otegui, Marisa S. AU - Otsu, Kinya AU - Ott, Christiane AU - Ottobrini, Luisa AU - Ou, Jing Hsiung James AU - Outeiro, Tiago F. AU - Oynebraten, Inger AU - Ozturk, Melek AU - Pagès, Gilles AU - Pahari, Susanta AU - Pajares, Marta AU - Pajvani, Utpal B. AU - Pal, Rituraj AU - Paladino, Simona AU - Pallet, Nicolas AU - Palmieri, Michela AU - Palmisano, Giuseppe AU - Palumbo, Camilla AU - Pampaloni, Francesco AU - Pan, Lifeng AU - Pan, Qingjun AU - Pan, Wenliang AU - Pan, Xin AU - Panasyuk, Ganna AU - Pandey, Rahul AU - Pandey, Udai B. AU - Pandya, Vrajesh AU - Paneni, Francesco AU - Pang, Shirley Y. AU - Panzarini, Elisa AU - Papademetrio, Daniela L. AU - Papaleo, Elena AU - Papinski, Daniel AU - Papp, Diana AU - Park, Eun Chan AU - Park, Hwan Tae AU - Park, Ji Man AU - Park, Jong In AU - Park, Joon Tae AU - Park, Junsoo AU - Park, Sang Chul AU - Park, Sang Youel AU - Parola, Abraham H. AU - Parys, Jan B. AU - Pasquier, Adrien AU - Pasquier, Benoit AU - Passos, João F. AU - Pastore, Nunzia AU - Patel, Hemal H. AU - Patschan, Daniel AU - Pattingre, Sophie AU - Pedraza-Alva, Gustavo AU - Pedraza-Chaverri, Jose AU - Pedrozo, Zully AU - Pei, Gang AU - Pei, Jianming AU - Peled-Zehavi, Hadas AU - Pellegrini, Joaquín M. AU - Pelletier, Joffrey AU - Peñalva, Miguel A. AU - Peng, Di AU - Peng, Ying AU - Penna, Fabio AU - Pennuto, Maria AU - Pentimalli, Francesca AU - Pereira, Cláudia M.F. AU - Pereira, Gustavo J.S. AU - Pereira, Lilian C. AU - Pereira De Almeida, Luis AU - Perera, Nirma D. AU - Pérez-Lara, Ángel AU - Perez-Oliva, Ana B. AU - Pérez-Pérez, María Esther AU - Periyasamy, Palsamy AU - Perl, Andras AU - Perrotta, Cristiana AU - Perrotta, Ida AU - Pestell, Richard G. AU - Petersen, Morten AU - Petrache, Irina AU - Petrovski, Goran AU - Pfirrmann, Thorsten AU - Pfister, Astrid S. AU - Philips, Jennifer A. AU - Pi, Huifeng AU - Picca, Anna AU - Pickrell, Alicia M. AU - Picot, Sandy AU - Pierantoni, Giovanna M. AU - Pierdominici, Marina AU - Pierre, Philippe AU - Pierrefite-Carle, Valérie AU - Pierzynowska, Karolina AU - Pietrocola, Federico AU - Pietruczuk, Miroslawa AU - Pignata, Claudio AU - Pimentel-Muiños, Felipe X. AU - Pinar, Mario AU - Pinheiro, Roberta O. AU - Pinkas-Kramarski, Ronit AU - Pinton, Paolo AU - Pircs, Karolina AU - Piya, Sujan AU - Pizzo, Paola AU - Plantinga, Theo S. AU - Platta, Harald W. AU - Plaza-Zabala, Ainhoa AU - Plomann, Markus AU - Plotnikov, Egor Y. AU - Plun-Favreau, Helene AU - Pluta, Ryszard AU - Pocock, Roger AU - Pöggeler, Stefanie AU - Pohl, Christian AU - Poirot, Marc AU - Poletti, Angelo AU - Ponpuak, Marisa AU - Popelka, Hana AU - Popova, Blagovesta AU - Porta, Helena AU - Porte Alcon, Soledad AU - Portilla-Fernandez, Eliana AU - Post, Martin AU - Potts, Malia B. AU - Poulton, Joanna AU - Powers, Ted AU - Prahlad, Veena AU - Prajsnar, Tomasz K. AU - Praticò, Domenico AU - Prencipe, Rosaria AU - Priault, Muriel AU - Proikas-Cezanne, Tassula AU - Promponas, Vasilis J. AU - Proud, Christopher G. AU - Puertollano, Rosa AU - Puglielli, Luigi AU - Pulinilkunnil, Thomas AU - Puri, Deepika AU - Puri, Rajat AU - Puyal, Julien AU - Qi, Xiaopeng AU - Qi, Yongmei AU - Qian, Wenbin AU - Qiang, Lei AU - Qiu, Yu AU - Quadrilatero, Joe AU - Quarleri, Jorge AU - Raben, Nina AU - Rabinowich, Hannah AU - Ragona, Debora AU - Ragusa, Michael J. AU - Rahimi, Nader AU - Rahmati, Marveh AU - Raia, Valeria AU - Raimundo, Nuno AU - Rajasekaran, Namakkal Soorappan AU - Ramachandra Rao, Sriganesh AU - Rami, Abdelhaq AU - Ramírez-Pardo, Ignacio AU - Ramsden, David B. AU - Randow, Felix AU - Rangarajan, Pundi N. AU - Ranieri, Danilo AU - Rao, Hai AU - Rao, Lang AU - Rao, Rekha AU - Rathore, Sumit AU - Ratnayaka, J. Arjuna AU - Ratovitski, Edward A. AU - Ravanan, Palaniyandi AU - Ravegnini, Gloria AU - Ray, Swapan K. AU - Razani, Babak AU - Rebecca, Vito AU - Reggiori, Fulvio AU - Régnier-Vigouroux, Anne AU - Reichert, Andreas S. AU - Reigada, David AU - Reiling, Jan H. AU - Rein, Theo AU - Reipert, Siegfried AU - Rekha, Rokeya Sultana AU - Ren, Hongmei AU - Ren, Jun AU - Ren, Weichao AU - Renault, Tristan AU - Renga, Giorgia AU - Reue, Karen AU - Rewitz, Kim AU - Ribeiro De Andrade Ramos, Bruna AU - Riazuddin, S. Amer AU - Ribeiro-Rodrigues, Teresa M. AU - Ricci, Jean Ehrland AU - Ricci, Romeo AU - Riccio, Victoria AU - Richardson, Des R. AU - Rikihisa, Yasuko AU - Risbud, Makarand V. AU - Risueño, Ruth M. AU - Ritis, Konstantinos AU - Rizza, Salvatore AU - Rizzuto, Rosario AU - Roberts, Helen C. AU - Roberts, Luke D. AU - Robinson, Katherine J. AU - Roccheri, Maria Carmela AU - Rocchi, Stephane AU - Rodney, George G. AU - Rodrigues, Tiago AU - Rodrigues Silva, Vagner Ramon AU - Rodriguez, Amaia AU - Rodriguez-Barrueco, Ruth AU - Rodriguez-Henche, Nieves AU - Rodriguez-Rocha, Humberto AU - Roelofs, Jeroen AU - Rogers, Robert S. AU - Rogov, Vladimir V. AU - Rojo, Ana I. AU - Rolka, Krzysztof AU - Romanello, Vanina AU - Romani, Luigina AU - Romano, Alessandra AU - Romano, Patricia S. AU - Romeo-Guitart, David AU - Romero, Luis C. AU - Romero, Montserrat AU - Roney, Joseph C. AU - Rongo, Christopher AU - Roperto, Sante AU - Rosenfeldt, Mathias T. AU - Rosenstiel, Philip AU - Rosenwald, Anne G. AU - Roth, Kevin A. AU - Roth, Lynn AU - Roth, Steven AU - Rouschop, Kasper M.A. AU - Roussel, Benoit D. AU - Roux, Sophie AU - Rovere-Querini, Patrizia AU - Roy, Ajit AU - Rozieres, Aurore AU - Ruano, Diego AU - Rubinsztein, David C. AU - Rubtsova, Maria P. AU - Ruckdeschel, Klaus AU - Ruckenstuhl, Christoph AU - Rudolf, Emil AU - Rudolf, Rüdiger AU - Ruggieri, Alessandra AU - Ruparelia, Avnika Ashok AU - Rusmini, Paola AU - Russell, Ryan R. AU - Russo, Gian Luigi AU - Russo, Maria AU - Russo, Rossella AU - Ryabaya, Oxana O. AU - Ryan, Kevin M. AU - Ryu, Kwon Yul AU - Sabater-Arcis, Maria AU - Sachdev, Ulka AU - Sacher, Michael AU - Sachse, Carsten AU - Sadhu, Abhishek AU - Sadoshima, Junichi AU - Safren, Nathaniel AU - Saftig, Paul AU - Sagona, Antonia P. AU - Sahay, Gaurav AU - Sahebkar, Amirhossein AU - Sahin, Mustafa AU - Sahin, Ozgur AU - Sahni, Sumit AU - Saito, Nayuta AU - Saito, Shigeru AU - Saito, Tsunenori AU - Sakai, Ryohei AU - Sakai, Yasuyoshi AU - Sakamaki, Jun Ichi AU - Saksela, Kalle AU - Salazar, Gloria AU - Salazar-Degracia, Anna AU - Salekdeh, Ghasem H. AU - Saluja, Ashok K. AU - Sampaio-Marques, Belém AU - Sanchez, Maria Cecilia AU - Sanchez-Alcazar, Jose A. AU - Sanchez-Vera, Victoria AU - Sancho-Shimizu, Vanessa AU - Sanderson, J. Thomas AU - Sandri, Marco AU - Santaguida, Stefano AU - Santambrogio, Laura AU - Santana, Magda M. AU - Santoni, Giorgio AU - Sanz, Alberto AU - Sanz, Pascual AU - Saran, Shweta AU - Sardiello, Marco AU - Sargeant, Timothy J. AU - Sarin, Apurva AU - Sarkar, Chinmoy AU - Sarkar, Sovan AU - Sarrias, Maria Rosa AU - Sarkar, Surajit AU - Sarmah, Dipanka Tanu AU - Sarparanta, Jaakko AU - Sathyanarayan, Aishwarya AU - Sathyanarayanan, Ranganayaki AU - Scaglione, K. Matthew AU - Scatozza, Francesca AU - Schaefer, Liliana AU - Schafer, Zachary T. AU - Schaible, Ulrich E. AU - Schapira, Anthony H.V. AU - Scharl, Michael AU - Schatzl, Hermann M. AU - Schein, Catherine H. AU - Scheper, Wiep AU - Scheuring, David AU - Schiaffino, Maria Vittoria AU - Schiappacassi, Monica AU - Schindl, Rainer AU - Schlattner, Uwe AU - Schmidt, Oliver AU - Schmitt, Roland AU - Schmidt, Stephen D. AU - Schmitz, Ingo AU - Schmukler, Eran AU - Schneider, Anja AU - Schneider, Bianca E. AU - Schober, Romana AU - Schoijet, Alejandra C. AU - Schott, Micah B. AU - Schramm, Michael AU - Schröder, Bernd AU - Schuh, Kai AU - Schüller, Christoph AU - Schulze, Ryan J. AU - Schürmanns, Lea AU - Schwamborn, Jens C. AU - Schwarten, Melanie AU - Scialo, Filippo AU - Sciarretta, Sebastiano AU - Scott, Melanie J. AU - Scotto, Kathleen W. AU - Scovassi, A. Ivana AU - Scrima, Andrea AU - Scrivo, Aurora AU - Sebastian, David AU - Sebti, Salwa AU - Sedej, Simon AU - Segatori, Laura AU - Segev, Nava AU - Seglen, Per O. AU - Seiliez, Iban AU - Seki, Ekihiro AU - Selleck, Scott B. AU - Sellke, Frank W. AU - Selsby, Joshua T. AU - Sendtner, Michael AU - Senturk, Serif AU - Seranova, Elena AU - Sergi, Consolato AU - Serra-Moreno, Ruth AU - Sesaki, Hiromi AU - Settembre, Carmine AU - Setty, Subba Rao Gangi AU - Sgarbi, Gianluca AU - Sha, Ou AU - Shacka, John J. AU - Shah, Javeed A. AU - Shang, Dantong AU - Shao, Changshun AU - Shao, Feng AU - Sharbati, Soroush AU - Sharkey, Lisa M. AU - Sharma, Dipali AU - Sharma, Gaurav AU - Sharma, Kulbhushan AU - Sharma, Pawan AU - Sharma, Surendra AU - Shen, Han Ming AU - Shen, Hongtao AU - Shen, Jiangang AU - Shen, Ming AU - Shen, Weili AU - Shen, Zheni AU - Sheng, Rui AU - Sheng, Zhi AU - Sheng, Zu Hang AU - Shi, Jianjian AU - Shi, Xiaobing AU - Shi, Ying Hong AU - Shiba-Fukushima, Kahori AU - Shieh, Jeng Jer AU - Shimada, Yohta AU - Shimizu, Shigeomi AU - Shimozawa, Makoto AU - Shintani, Takahiro AU - Shoemaker, Christopher J. AU - Shojaei, Shahla AU - Shoji, Ikuo AU - Shravage, Bhupendra V. AU - Shridhar, Viji AU - Shu, Chih Wen AU - Shu, Hong Bing AU - Shui, Ke AU - Shukla, Arvind K. AU - Shutt, Timothy E. AU - Sica, Valentina AU - Siddiqui, Aleem AU - Sierra, Amanda AU - Sierra-Torre, Virginia AU - Signorelli, Santiago AU - Sil, Payel AU - Silva, Bruno J.De Andrade AU - Silva, Johnatas D. AU - Silva-Pavez, Eduardo AU - Silvente-Poirot, Sandrine AU - Simmonds, Rachel E. AU - Simon, Anna Katharina AU - Simon, Hans Uwe AU - Simons, Matias AU - Singh, Anurag AU - Singh, Lalit P. AU - Singh, Rajat AU - Singh, Shivendra V. AU - Singh, Shrawan K. AU - Singh, Sudha B. AU - Singh, Sunaina AU - Singh, Surinder Pal AU - Sinha, Debasish AU - Sinha, Rohit Anthony AU - Sinha, Sangita AU - Sirko, Agnieszka AU - Sirohi, Kapil AU - Sivridis, Efthimios L. AU - Skendros, Panagiotis AU - Skirycz, Aleksandra AU - Slaninová, Iva AU - Smaili, Soraya S. AU - Smertenko, Andrei AU - Smith, Matthew D. AU - Soenen, Stefaan J. AU - Sohn, Eun Jung AU - Sok, Sophia P.M. AU - Solaini, Giancarlo AU - Soldati, Thierry AU - Soleimanpour, Scott A. AU - Soler, Rosa M. AU - Solovchenko, Alexei AU - Somarelli, Jason A. AU - Sonawane, Avinash AU - Song, Fuyong AU - Song, Hyun Kyu AU - Song, Ju Xian AU - Song, Kunhua AU - Song, Zhiyin AU - Soria, Leandro R. AU - Sorice, Maurizio AU - Soukas, Alexander A. AU - Soukup, Sandra Fausia AU - Sousa, Diana AU - Sousa, Nadia AU - Spagnuolo, Paul A. AU - Spector, Stephen A. AU - Srinivas Bharath, M. M. AU - St. Clair, Daret AU - Stagni, Venturina AU - Staiano, Leopoldo AU - Stalnecker, Clint A. AU - Stankov, Metodi V. AU - Stathopulos, Peter B. AU - Stefan, Katja AU - Stefan, Sven Marcel AU - Stefanis, Leonidas AU - Steffan, Joan S. AU - Steinkasserer, Alexander AU - Stenmark, Harald AU - Sterneckert, Jared AU - Stevens, Craig AU - Stoka, Veronika AU - Storch, Stephan AU - Stork, Björn AU - Strappazzon, Flavie AU - Strohecker, Anne Marie AU - Stupack, Dwayne G. AU - Su, Huanxing AU - Su, Ling Yan AU - Su, Longxiang AU - Suarez-Fontes, Ana M. AU - Subauste, Carlos S. AU - Subbian, Selvakumar AU - Subirada, Paula V. AU - Sudhandiran, Ganapasam AU - Sue, Carolyn M. AU - Sui, Xinbing AU - Summers, Corey AU - Sun, Guangchao AU - Sun, Jun AU - Sun, Kang AU - Sun, Meng Xiang AU - Sun, Qiming AU - Sun, Yi AU - Sun, Zhongjie AU - Sunahara, Karen K.S. AU - Sundberg, Eva AU - Susztak, Katalin AU - Sutovsky, Peter AU - Suzuki, Hidekazu AU - Sweeney, Gary AU - Symons, J. David AU - Sze, Stephen Cho Wing AU - Szewczyk, Nathaniel J. AU - Tabęcka-Łonczynska, Anna AU - Tabolacci, Claudio AU - Tacke, Frank AU - Taegtmeyer, Heinrich AU - Tafani, Marco AU - Tagaya, Mitsuo AU - Tai, Haoran AU - Tait, Stephen W.G. AU - Takahashi, Yoshinori AU - Takats, Szabolcs AU - Talwar, Priti AU - Tam, Chit AU - Tam, Shing Yau AU - Tampellini, Davide AU - Tamura, Atsushi AU - Tan, Chong Teik AU - Tan, Eng King AU - Tan, Ya Qin AU - Tanaka, Masaki AU - Tanaka, Motomasa AU - Tang, Daolin AU - Tang, Jingfeng AU - Tang, Tie Shan AU - Tanida, Isei AU - Tao, Zhipeng AU - Taouis, Mohammed AU - Tatenhorst, Lars AU - Tavernarakis, Nektarios AU - Taylor, Allen AU - Taylor, Gregory A. AU - Taylor, Joan M. AU - Tchetina, Elena AU - Tee, Andrew R. AU - Tegeder, Irmgard AU - Teis, David AU - Teixeira, Natercia AU - Teixeira-Clerc, Fatima AU - Tekirdag, Kumsal A. AU - Tencomnao, Tewin AU - Tenreiro, Sandra AU - Tepikin, Alexei V. AU - Testillano, Pilar S. AU - Tettamanti, Gianluca AU - Tharaux, Pierre Louis AU - Thedieck, Kathrin AU - Thekkinghat, Arvind A. AU - Thellung, Stefano AU - Thinwa, Josephine W. AU - Thirumalaikumar, V. P. AU - Thomas, Sufi Mary AU - Thomes, Paul G. AU - Thorburn, Andrew AU - Thukral, Lipi AU - Thum, Thomas AU - Thumm, Michael AU - Tian, Ling AU - Tichy, Ales AU - Till, Andreas AU - Timmerman, Vincent AU - Titorenko, Vladimir I. AU - Todi, Sokol V. AU - Todorova, Krassimira AU - Toivonen, Janne M. AU - Tomaipitinca, Luana AU - Tomar, Dhanendra AU - Tomas-Zapico, Cristina AU - Tomić, Sergej AU - Tong, Benjamin Chun Kit AU - Tong, Chao AU - Tong, Xin AU - Tooze, Sharon A. AU - Torgersen, Maria L. AU - Torii, Satoru AU - Torres-López, Liliana AU - Torriglia, Alicia AU - Towers, Christina G. AU - Towns, Roberto AU - Toyokuni, Shinya AU - Trajkovic, Vladimir AU - Tramontano, Donatella AU - Tran, Quynh Giao AU - Travassos, Leonardo H. AU - Trelford, Charles B. AU - Tremel, Shirley AU - Trougakos, Ioannis P. AU - Tsao, Betty P. AU - Tschan, Mario P. AU - Tse, Hung Fat AU - Tse, Tak Fu AU - Tsugawa, Hitoshi AU - Tsvetkov, Andrey S. AU - Tumbarello, David A. AU - Tumtas, Yasin AU - Tuñón, María J. AU - Turcotte, Sandra AU - Turk, Boris AU - Turk, Vito AU - Turner, Bradley J. AU - Tuxworth, Richard I. AU - Tyler, Jessica K. AU - Tyutereva, Elena V. AU - Uchiyama, Yasuo AU - Ugun-Klusek, Aslihan AU - Uhlig, Holm H. AU - Ułamek-Kozioł, Marzena AU - Ulasov, Ilya V. AU - Umekawa, Midori AU - Ungermann, Christian AU - Unno, Rei AU - Urbe, Sylvie AU - Uribe-Carretero, Elisabet AU - Üstün, Suayib AU - Uversky, Vladimir N. AU - Vaccari, Thomas AU - Vaccaro, Maria I. AU - Vahsen, Björn F. AU - Vakifahmetoglu-Norberg, Helin AU - Valdor, Rut AU - Valente, Maria J. AU - Valko, Ayelén AU - Vallee, Richard B. AU - Valverde, Angela M. AU - Van Den Berghe, Greet AU - Van Der Veen, Stijn AU - Van Kaer, Luc AU - Van Loosdregt, Jorg AU - Van Wijk, Sjoerd J.L. AU - Vandenberghe, Wim AU - Vanhorebeek, Ilse AU - Vannier-Santos, Marcos A. AU - Vannini, Nicola AU - Vanrell, M. Cristina AU - Vantaggiato, Chiara AU - Varano, Gabriele AU - Varela-Nieto, Isabel AU - Varga, Máté AU - Vasconcelos, M. Helena AU - Vats, Somya AU - Vavvas, Demetrios G. AU - Vega-Naredo, Ignacio AU - Vega-Rubin-De-Celis, Silvia AU - Velasco, Guillermo AU - Velázquez, Ariadna P. AU - Vellai, Tibor AU - Vellenga, Edo AU - Velotti, Francesca AU - Verdier, Mireille AU - Verginis, Panayotis AU - Vergne, Isabelle AU - Verkade, Paul AU - Verma, Manish AU - Verstreken, Patrik AU - Vervliet, Tim AU - Vervoorts, Jörg AU - Vessoni, Alexandre T. AU - Victor, Victor M. AU - Vidal, Michel AU - Vidoni, Chiara AU - Vieira, Otilia V. AU - Vierstra, Richard D. AU - Viganó, Sonia AU - Vihinen, Helena AU - Vijayan, Vinoy AU - Vila, Miquel AU - Vilar, Marçal AU - Villalba, José M. AU - Villalobo, Antonio AU - Villarejo-Zori, Beatriz AU - Villarroya, Francesc AU - Villarroya, Joan AU - Vincent, Olivier AU - Vindis, Cecile AU - Viret, Christophe AU - Viscomi, Maria Teresa AU - Visnjic, Dora AU - Vitale, Ilio AU - Vocadlo, David J. AU - Voitsekhovskaja, Olga V. AU - Volonté, Cinzia AU - Volta, Mattia AU - Vomero, Marta AU - Von Haefen, Clarissa AU - Vooijs, Marc A. AU - Voos, Wolfgang AU - Vucicevic, Ljubica AU - Wade-Martins, Richard AU - Waguri, Satoshi AU - Waite, Kenrick A. AU - Wakatsuki, Shuji AU - Walker, David W. AU - Walker, Mark J. AU - Walker, Simon A. AU - Walter, Jochen AU - Wandosell, Francisco G. AU - Wang, Bo AU - Wang, Chao Yung AU - Wang, Chen AU - Wang, Chenran AU - Wang, Chenwei AU - Wang, Cun Yu AU - Wang, Dong AU - Wang, Fangyang AU - Wang, Feng AU - Wang, Fengming AU - Wang, Guansong AU - Wang, Han AU - Wang, Hao AU - Wang, Hexiang AU - Wang, Hong Gang AU - Wang, Jianrong AU - Wang, Jigang AU - Wang, Jiou AU - Wang, Jundong AU - Wang, Kui AU - Wang, Lianrong AU - Wang, Liming AU - Wang, Maggie Haitian AU - Wang, Meiqing AU - Wang, Nanbu AU - Wang, Pengwei AU - Wang, Peipei AU - Wang, Ping AU - Wang, Ping AU - Wang, Qing Jun AU - Wang, Qing AU - Wang, Qing Kenneth AU - Wang, Qiong A. AU - Wang, Wen Tao AU - Wang, Wuyang AU - Wang, Xinnan AU - Wang, Xuejun AU - Wang, Yan AU - Wang, Yanchang AU - Wang, Yanzhuang AU - Wang, Yen Yun AU - Wang, Yihua AU - Wang, Yipeng AU - Wang, Yu AU - Wang, Yuqi AU - Wang, Zhe AU - Wang, Zhenyu AU - Wang, Zhouguang AU - Warnes, Gary AU - Warnsmann, Verena AU - Watada, Hirotaka AU - Watanabe, Eizo AU - Watchon, Maxinne AU - Wawrzyńska, Anna AU - Weaver, Timothy E. AU - Wegrzyn, Grzegorz AU - Wehman, Ann M. AU - Wei, Huafeng AU - Wei, Lei AU - Wei, Taotao AU - Wei, Yongjie AU - Weiergräber, Oliver H. AU - Weihl, Conrad C. AU - Weindl, Günther AU - Weiskirchen, Ralf AU - Wells, Alan AU - Wen, Runxia H. AU - Wen, Xin AU - Werner, Antonia AU - Weykopf, Beatrice AU - Wheatley, Sally P. AU - Whitton, J. Lindsay AU - Whitworth, Alexander J. AU - Wiktorska, Katarzyna AU - Wildenberg, Manon E. AU - Wileman, Tom AU - Wilkinson, Simon AU - Willbold, Dieter AU - Williams, Brett AU - Williams, Robin S.B. AU - Williams, Roger L. AU - Williamson, Peter R. AU - Wilson, Richard A. AU - Winner, Beate AU - Winsor, Nathaniel J. AU - Witkin, Steven S. AU - Wodrich, Harald AU - Woehlbier, Ute AU - Wollert, Thomas AU - Wong, Esther AU - Wong, Jack Ho AU - Wong, Richard W. AU - Wong, Vincent Kam Wai AU - Wong, W. Wei Lynn AU - Wu, An Guo AU - Wu, Chengbiao AU - Wu, Jian AU - Wu, Junfang AU - Wu, Kenneth K. AU - Wu, Min AU - Wu, Shan Ying AU - Wu, Shengzhou AU - Wu, Shu Yan AU - Wu, Shufang AU - Wu, William K.K. AU - Wu, Xiaohong AU - Wu, Xiaoqing AU - Wu, Yao Wen AU - Wu, Yihua AU - Xavier, Ramnik J. AU - Xia, Hongguang AU - Xia, Lixin AU - Xia, Zhengyuan AU - Xiang, Ge AU - Xiang, Jin AU - Xiang, Mingliang AU - Xiang, Wei AU - Xiao, Bin AU - Xiao, Guozhi AU - Xiao, Hengyi AU - Xiao, Hong Tao AU - Xiao, Jian AU - Xiao, Lan AU - Xiao, Shi AU - Xiao, Yin AU - Xie, Baoming AU - Xie, Chuan Ming AU - Xie, Min AU - Xie, Yuxiang AU - Xie, Zhiping AU - Xie, Zhonglin AU - Xilouri, Maria AU - Xu, Congfeng AU - Xu, En AU - Xu, Haoxing AU - Xu, Jing AU - Xu, Jin Rong AU - Xu, Liang AU - Xu, Wen Wen AU - Xu, Xiulong AU - Xue, Yu AU - Yakhine-Diop, Sokhna M.S. AU - Yamaguchi, Masamitsu AU - Yamaguchi, Osamu AU - Yamamoto, Ai AU - Yamashina, Shunhei AU - Yan, Shengmin AU - Yan, Shian Jang AU - Yan, Zhen AU - Yanagi, Yasuo AU - Yang, Chuanbin AU - Yang, Dun Sheng AU - Yang, Huan AU - Yang, Huang Tian AU - Yang, Hui AU - Yang, Jin Ming AU - Yang, Jing AU - Yang, Jingyu AU - Yang, Ling AU - Yang, Liu AU - Yang, Ming AU - Yang, Pei Ming AU - Yang, Qian AU - Yang, Seungwon AU - Yang, Shu AU - Yang, Shun Fa AU - Yang, Wannian AU - Yang, Wei Yuan AU - Yang, Xiaoyong AU - Yang, Xuesong AU - Yang, Yi AU - Yang, Ying AU - Yao, Honghong AU - Yao, Shenggen AU - Yao, Xiaoqiang AU - Yao, Yong Gang AU - Yao, Yong Ming AU - Yasui, Takahiro AU - Yazdankhah, Meysam AU - Yen, Paul M. AU - Yi, Cong AU - Yin, Xiao Ming AU - Yin, Yanhai AU - Yin, Zhangyuan AU - Yin, Ziyi AU - Ying, Meidan AU - Ying, Zheng AU - Yip, Calvin K. AU - Yiu, Stephanie Pei Tung AU - Yoo, Young H. AU - Yoshida, Kiyotsugu AU - Yoshii, Saori R. AU - Yoshimori, Tamotsu AU - Yousefi, Bahman AU - Yu, Boxuan AU - Yu, Haiyang AU - Yu, Jun AU - Yu, Jun AU - Yu, Li AU - Yu, Ming Lung AU - Yu, Seong Woon AU - Yu, Victor C. AU - Yu, W. Haung AU - Yu, Zhengping AU - Yu, Zhou AU - Yuan, Junying AU - Yuan, Ling Qing AU - Yuan, Shilin AU - Yuan, Shyng Shiou F. AU - Yuan, Yanggang AU - Yuan, Zengqiang AU - Yue, Jianbo AU - Yue, Zhenyu AU - Yun, Jeanho AU - Yung, Raymond L. AU - Zacks, David N. AU - Zaffagnini, Gabriele AU - Zambelli, Vanessa O. AU - Zanella, Isabella AU - Zang, Qun S. AU - Zanivan, Sara AU - Zappavigna, Silvia AU - Zaragoza, Pilar AU - Zarbalis, Konstantinos S. AU - Zarebkohan, Amir AU - Zarrouk, Amira AU - Zeitlin, Scott O. AU - Zeng, Jialiu AU - Zeng, Ju Deng AU - Žerovnik, Eva AU - Zhan, Lixuan AU - Zhang, Bin AU - Zhang, Donna D. AU - Zhang, Hanlin AU - Zhang, Hong AU - Zhang, Hong AU - Zhang, Honghe AU - Zhang, Huafeng AU - Zhang, Huaye AU - Zhang, Hui AU - Zhang, Hui Ling AU - Zhang, Jianbin AU - Zhang, Jianhua AU - Zhang, Jing Pu AU - Zhang, Kalin Y.B. AU - Zhang, Leshuai W. AU - Zhang, Lin AU - Zhang, Lisheng AU - Zhang, Lu AU - Zhang, Luoying AU - Zhang, Menghuan AU - Zhang, Peng AU - Zhang, Sheng AU - Zhang, Wei AU - Zhang, Xiangnan AU - Zhang, Xiao Wei AU - Zhang, Xiaolei AU - Zhang, Xiaoyan AU - Zhang, Xin AU - Zhang, Xinxin AU - Zhang, Xu Dong AU - Zhang, Yang AU - Zhang, Yanjin AU - Zhang, Yi AU - Zhang, Ying Dong AU - Zhang, Yingmei AU - Zhang, Yuan Yuan AU - Zhang, Yuchen AU - Zhang, Zhe AU - Zhang, Zhengguang AU - Zhang, Zhibing AU - Zhang, Zhihai AU - Zhang, Zhiyong AU - Zhang, Zili AU - Zhao, Haobin AU - Zhao, Lei AU - Zhao, Shuang AU - Zhao, Tongbiao AU - Zhao, Xiao Fan AU - Zhao, Ying AU - Zhao, Yongchao AU - Zhao, Yongliang AU - Zhao, Yuting AU - Zheng, Guoping AU - Zheng, Kai AU - Zheng, Ling AU - Zheng, Shizhong AU - Zheng, Xi Long AU - Zheng, Yi AU - Zheng, Zu Guo AU - Zhivotovsky, Boris AU - Zhong, Qing AU - Zhou, Ao AU - Zhou, Ben AU - Zhou, Cefan AU - Zhou, Gang AU - Zhou, Hao AU - Zhou, Hong AU - Zhou, Hongbo AU - Zhou, Jie AU - Zhou, Jing AU - Zhou, Jing AU - Zhou, Jiyong AU - Zhou, Kailiang AU - Zhou, Rongjia AU - Zhou, Xu Jie AU - Zhou, Yanshuang AU - Zhou, Yinghong AU - Zhou, Yubin AU - Zhou, Zheng Yu AU - Zhou, Zhou AU - Zhu, Binglin AU - Zhu, Changlian AU - Zhu, Guo Qing AU - Zhu, Haining AU - Zhu, Hongxin AU - Zhu, Hua AU - Zhu, Wei Guo AU - Zhu, Yanping AU - Zhu, Yushan AU - Zhuang, Haixia AU - Zhuang, Xiaohong AU - Zientara-Rytter, Katarzyna AU - Zimmermann, Christine M. AU - Ziviani, Elena AU - Zoladek, Teresa AU - Zong, Wei Xing AU - Zorov, Dmitry B. AU - Zorzano, Antonio AU - Zou, Weiping AU - Zou, Zhen AU - Zou, Zhengzhi AU - Zuryn, Steven AU - Zwerschke, Werner AU - Brand-Saberi, Beate AU - Dong, X. Charlie AU - Kenchappa, Chandra Shekar AU - Li, Zuguo AU - Lin, Yong AU - Oshima, Shigeru AU - Rong, Yueguang AU - Sluimer, Judith C. AU - Stallings, Christina L. AU - Tong, Chun Kit ID - 9298 IS - 1 JF - Autophagy SN - 1554-8627 TI - Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) VL - 17 ER - TY - JOUR AB - Growth regulation tailors development in plants to their environment. A prominent example of this is the response to gravity, in which shoots bend up and roots bend down1. This paradox is based on opposite effects of the phytohormone auxin, which promotes cell expansion in shoots while inhibiting it in roots via a yet unknown cellular mechanism2. Here, by combining microfluidics, live imaging, genetic engineering and phosphoproteomics in Arabidopsis thaliana, we advance understanding of how auxin inhibits root growth. We show that auxin activates two distinct, antagonistically acting signalling pathways that converge on rapid regulation of apoplastic pH, a causative determinant of growth. Cell surface-based TRANSMEMBRANE KINASE1 (TMK1) interacts with and mediates phosphorylation and activation of plasma membrane H+-ATPases for apoplast acidification, while intracellular canonical auxin signalling promotes net cellular H+ influx, causing apoplast alkalinization. Simultaneous activation of these two counteracting mechanisms poises roots for rapid, fine-tuned growth modulation in navigating complex soil environments. AU - Li, Lanxin AU - Verstraeten, Inge AU - Roosjen, Mark AU - Takahashi, Koji AU - Rodriguez Solovey, Lesia AU - Merrin, Jack AU - Chen, Jian AU - Shabala, Lana AU - Smet, Wouter AU - Ren, Hong AU - Vanneste, Steffen AU - Shabala, Sergey AU - De Rybel, Bert AU - Weijers, Dolf AU - Kinoshita, Toshinori AU - Gray, William M. AU - Friml, Jiří ID - 10223 IS - 7884 JF - Nature KW - Multidisciplinary SN - 00280836 TI - Cell surface and intracellular auxin signalling for H+ fluxes in root growth VL - 599 ER - TY - JOUR AB - Transposable elements exist widely throughout plant genomes and play important roles in plant evolution. Auxin is an important regulator that is traditionally associated with root development and drought stress adaptation. The DEEPER ROOTING 1 (DRO1) gene is a key component of rice drought avoidance. Here, we identified a transposon that acts as an autonomous auxin‐responsive promoter and its presence at specific genome positions conveys physiological adaptations related to drought avoidance. Rice varieties with high and auxin‐mediated transcription of DRO1 in the root tip show deeper and longer root phenotypes and are thus better adapted to drought. The INDITTO2 transposon contains an auxin response element and displays auxin‐responsive promoter activity; it is thus able to convey auxin regulation of transcription to genes in its proximity. In the rice Acuce, which displays DRO1‐mediated drought adaptation, the INDITTO2 transposon was found to be inserted at the promoter region of the DRO1 locus. Transgenesis‐based insertion of the INDITTO2 transposon into the DRO1 promoter of the non‐adapted rice variety Nipponbare was sufficient to promote its drought avoidance. Our data identify an example of how transposons can act as promoters and convey hormonal regulation to nearby loci, improving plant fitness in response to different abiotic stresses. AU - Zhao, Y AU - Wu, L AU - Fu, Q AU - Wang, D AU - Li, J AU - Yao, B AU - Yu, S AU - Jiang, L AU - Qian, J AU - Zhou, X AU - Han, L AU - Zhao, S AU - Ma, C AU - Zhang, Y AU - Luo, C AU - Dong, Q AU - Li, S AU - Zhang, L AU - Jiang, X AU - Li, Y AU - Luo, H AU - Li, K AU - Yang, J AU - Luo, Q AU - Li, L AU - Peng, S AU - Huang, H AU - Zuo, Z AU - Liu, C AU - Wang, L AU - Li, C AU - He, X AU - Friml, Jiří AU - Du, Y ID - 9189 IS - 6 JF - Plant, Cell & Environment SN - 0140-7791 TI - INDITTO2 transposon conveys auxin-mediated DRO1 transcription for rice drought avoidance VL - 44 ER - TY - JOUR AB - Clathrin-mediated endocytosis is the major route of entry of cargos into cells and thus underpins many physiological processes. During endocytosis, an area of flat membrane is remodeled by proteins to create a spherical vesicle against intracellular forces. The protein machinery which mediates this membrane bending in plants is unknown. However, it is known that plant endocytosis is actin independent, thus indicating that plants utilize a unique mechanism to mediate membrane bending against high-turgor pressure compared to other model systems. Here, we investigate the TPLATE complex, a plant-specific endocytosis protein complex. It has been thought to function as a classical adaptor functioning underneath the clathrin coat. However, by using biochemical and advanced live microscopy approaches, we found that TPLATE is peripherally associated with clathrin-coated vesicles and localizes at the rim of endocytosis events. As this localization is more fitting to the protein machinery involved in membrane bending during endocytosis, we examined cells in which the TPLATE complex was disrupted and found that the clathrin structures present as flat patches. This suggests a requirement of the TPLATE complex for membrane bending during plant clathrin–mediated endocytosis. Next, we used in vitro biophysical assays to confirm that the TPLATE complex possesses protein domains with intrinsic membrane remodeling activity. These results redefine the role of the TPLATE complex and implicate it as a key component of the evolutionarily distinct plant endocytosis mechanism, which mediates endocytic membrane bending against the high-turgor pressure in plant cells. AU - Johnson, Alexander J AU - Dahhan, Dana A AU - Gnyliukh, Nataliia AU - Kaufmann, Walter AU - Zheden, Vanessa AU - Costanzo, Tommaso AU - Mahou, Pierre AU - Hrtyan, Mónika AU - Wang, Jie AU - Aguilera Servin, Juan L AU - van Damme, Daniël AU - Beaurepaire, Emmanuel AU - Loose, Martin AU - Bednarek, Sebastian Y AU - Friml, Jiří ID - 9887 IS - 51 JF - Proceedings of the National Academy of Sciences TI - The TPLATE complex mediates membrane bending during plant clathrin-mediated endocytosis VL - 118 ER - TY - GEN AB - Raw data generated from the publication - The TPLATE complex mediates membrane bending during plant clathrin-mediated endocytosis by Johnson et al., 2021 In PNAS AU - Johnson, Alexander J ID - 14988 TI - Raw data from Johnson et al, PNAS, 2021 ER - TY - THES AB - Blood – this is what animals use to heal wounds fast and efficient. Plants do not have blood circulation and their cells cannot move. However, plants have evolved remarkable capacities to regenerate tissues and organs preventing further damage. In my PhD research, I studied the wound healing in the Arabidopsis root. I used a UV laser to ablate single cells in the root tip and observed the consequent wound healing. Interestingly, the inner adjacent cells induced a division plane switch and subsequently adopted the cell type of the killed cell to replace it. We termed this form of wound healing “restorative divisions”. This initial observation triggered the questions of my PhD studies: How and why do cells orient their division planes, how do they feel the wound and why does this happen only in inner adjacent cells. For answering these questions, I used a quite simple experimental setup: 5 day - old seedlings were stained with propidium iodide to visualize cell walls and dead cells; ablation was carried out using a special laser cutter and a confocal microscope. Adaptation of the novel vertical microscope system made it possible to observe wounds in real time. This revealed that restorative divisions occur at increased frequency compared to normal divisions. Additionally, the major plant hormone auxin accumulates in wound adjacent cells and drives the expression of the wound-stress responsive transcription factor ERF115. Using this as a marker gene for wound responses, we found that an important part of wound signalling is the sensing of the collapse of the ablated cell. The collapse causes a radical pressure drop, which results in strong tissue deformations. These deformations manifest in an invasion of the now free spot specifically by the inner adjacent cells within seconds, probably because of higher pressure of the inner tissues. Long-term imaging revealed that those deformed cells continuously expand towards the wound hole and that this is crucial for the restorative division. These wound-expanding cells exhibit an abnormal, biphasic polarity of microtubule arrays before the division. Experiments inhibiting cell expansion suggest that it is the biphasic stretching that induces those MT arrays. Adapting the micromanipulator aspiration system from animal scientists at our institute confirmed the hypothesis that stretching influences microtubule stability. In conclusion, this shows that microtubules react to tissue deformation and this facilitates the observed division plane switch. This puts mechanical cues and tensions at the most prominent position for explaining the growth and wound healing properties of plants. Hence, it shines light onto the importance of understanding mechanical signal transduction. AU - Hörmayer, Lukas ID - 9992 SN - 2663-337X TI - Wound healing in the Arabidopsis root meristem ER - TY - JOUR AB - Availability of the essential macronutrient nitrogen in soil plays a critical role in plant growth, development, and impacts agricultural productivity. Plants have evolved different strategies for sensing and responding to heterogeneous nitrogen distribution. Modulation of root system architecture, including primary root growth and branching, is among the most essential plant adaptions to ensure adequate nitrogen acquisition. However, the immediate molecular pathways coordinating the adjustment of root growth in response to distinct nitrogen sources, such as nitrate or ammonium, are poorly understood. Here, we show that growth as manifested by cell division and elongation is synchronized by coordinated auxin flux between two adjacent outer tissue layers of the root. This coordination is achieved by nitrate‐dependent dephosphorylation of the PIN2 auxin efflux carrier at a previously uncharacterized phosphorylation site, leading to subsequent PIN2 lateralization and thereby regulating auxin flow between adjacent tissues. A dynamic computer model based on our experimental data successfully recapitulates experimental observations. Our study provides mechanistic insights broadening our understanding of root growth mechanisms in dynamic environments. AU - Ötvös, Krisztina AU - Marconi, Marco AU - Vega, Andrea AU - O’Brien, Jose AU - Johnson, Alexander J AU - Abualia, Rashed AU - Antonielli, Livio AU - Montesinos López, Juan C AU - Zhang, Yuzhou AU - Tan, Shutang AU - Cuesta, Candela AU - Artner, Christina AU - Bouguyon, Eleonore AU - Gojon, Alain AU - Friml, Jiří AU - Gutiérrez, Rodrigo A. AU - Wabnik, Krzysztof T AU - Benková, Eva ID - 9010 IS - 3 JF - EMBO Journal SN - 02614189 TI - Modulation of plant root growth by nitrogen source-defined regulation of polar auxin transport VL - 40 ER - TY - JOUR AB - Auxin is a major plant growth regulator, but current models on auxin perception and signaling cannot explain the whole plethora of auxin effects, in particular those associated with rapid responses. A possible candidate for a component of additional auxin perception mechanisms is the AUXIN BINDING PROTEIN 1 (ABP1), whose function in planta remains unclear. Here we combined expression analysis with gain- and loss-of-function approaches to analyze the role of ABP1 in plant development. ABP1 shows a broad expression largely overlapping with, but not regulated by, transcriptional auxin response activity. Furthermore, ABP1 activity is not essential for the transcriptional auxin signaling. Genetic in planta analysis revealed that abp1 loss-of-function mutants show largely normal development with minor defects in bolting. On the other hand, ABP1 gain-of-function alleles show a broad range of growth and developmental defects, including root and hypocotyl growth and bending, lateral root and leaf development, bolting, as well as response to heat stress. At the cellular level, ABP1 gain-of-function leads to impaired auxin effect on PIN polar distribution and affects BFA-sensitive PIN intracellular aggregation. The gain-of-function analysis suggests a broad, but still mechanistically unclear involvement of ABP1 in plant development, possibly masked in abp1 loss-of-function mutants by a functional redundancy. AU - Gelová, Zuzana AU - Gallei, Michelle C AU - Pernisová, Markéta AU - Brunoud, Géraldine AU - Zhang, Xixi AU - Glanc, Matous AU - Li, Lanxin AU - Michalko, Jaroslav AU - Pavlovicova, Zlata AU - Verstraeten, Inge AU - Han, Huibin AU - Hajny, Jakub AU - Hauschild, Robert AU - Čovanová, Milada AU - Zwiewka, Marta AU - Hörmayer, Lukas AU - Fendrych, Matyas AU - Xu, Tongda AU - Vernoux, Teva AU - Friml, Jiří ID - 8931 JF - Plant Science KW - Agronomy and Crop Science KW - Plant Science KW - Genetics KW - General Medicine SN - 0168-9452 TI - Developmental roles of auxin binding protein 1 in Arabidopsis thaliana VL - 303 ER - TY - JOUR AB - The phytohormone auxin and its directional transport through tissues are intensively studied. However, a mechanistic understanding of auxin-mediated feedback on endocytosis and polar distribution of PIN auxin transporters remains limited due to contradictory observations and interpretations. Here, we used state-of-the-art methods to reexamine the auxin effects on PIN endocytic trafficking. We used high auxin concentrations or longer treatments versus lower concentrations and shorter treatments of natural (IAA) and synthetic (NAA) auxins to distinguish between specific and nonspecific effects. Longer treatments of both auxins interfere with Brefeldin A-mediated intracellular PIN2 accumulation and also with general aggregation of endomembrane compartments. NAA treatment decreased the internalization of the endocytic tracer dye, FM4-64; however, NAA treatment also affected the number, distribution, and compartment identity of the early endosome/trans-Golgi network (EE/TGN), rendering the FM4-64 endocytic assays at high NAA concentrations unreliable. To circumvent these nonspecific effects of NAA and IAA affecting the endomembrane system, we opted for alternative approaches visualizing the endocytic events directly at the plasma membrane (PM). Using Total Internal Reflection Fluorescence (TIRF) microscopy, we saw no significant effects of IAA or NAA treatments on the incidence and dynamics of clathrin foci, implying that these treatments do not affect the overall endocytosis rate. However, both NAA and IAA at low concentrations rapidly and specifically promoted endocytosis of photo-converted PIN2 from the PM. These analyses identify a specific effect of NAA and IAA on PIN2 endocytosis, thus contributing to its polarity maintenance and furthermore illustrate that high auxin levels have nonspecific effects on trafficking and endomembrane compartments. AU - Narasimhan, Madhumitha AU - Gallei, Michelle C AU - Tan, Shutang AU - Johnson, Alexander J AU - Verstraeten, Inge AU - Li, Lanxin AU - Rodriguez Solovey, Lesia AU - Han, Huibin AU - Himschoot, E AU - Wang, R AU - Vanneste, S AU - Sánchez-Simarro, J AU - Aniento, F AU - Adamowski, Maciek AU - Friml, Jiří ID - 9287 IS - 2 JF - Plant Physiology SN - 0032-0889 TI - Systematic analysis of specific and nonspecific auxin effects on endocytosis and trafficking VL - 186 ER - TY - THES AB - Plant motions occur across a wide spectrum of timescales, ranging from seed dispersal through bursting (milliseconds) and stomatal opening (minutes) to long-term adaptation of gross architecture. Relatively fast motions include water-driven growth as exemplified by root cell expansion under abiotic/biotic stresses or during gravitropism. A showcase is a root growth inhibition in 30 seconds triggered by the phytohormone auxin. However, the cellular and molecular mechanisms are still largely unknown. This thesis covers the studies about this topic as follows. By taking advantage of microfluidics combined with live imaging, pharmaceutical tools, and transgenic lines, we examined the kinetics of and causal relationship among various auxininduced rapid cellular changes in root growth, apoplastic pH, cytosolic Ca2+, cortical microtubule (CMT) orientation, and vacuolar morphology. We revealed that CMT reorientation and vacuolar constriction are the consequence of growth itself instead of responding directly to auxin. In contrast, auxin induces apoplast alkalinization to rapidly inhibit root growth in 30 seconds. This auxin-triggered apoplast alkalinization results from rapid H+- influx that is contributed by Ca2+ inward channel CYCLIC NUCLEOTIDE-GATED CHANNEL 14 (CNGC14)-dependent Ca2+ signaling. To dissect which auxin signaling mediates the rapid apoplast alkalinization, we combined microfluidics and genetic engineering to verify that TIR1/AFB receptors conduct a non-transcriptional regulation on Ca2+ and H+ -influx. This non-canonical pathway is mostly mediated by the cytosolic portion of TIR1/AFB. On the other hand, we uncovered, using biochemical and phospho-proteomic analysis, that auxin cell surface signaling component TRANSMEMBRANE KINASE 1 (TMK1) plays a negative role during auxin-trigger apoplast alkalinization and root growth inhibition through directly activating PM H+ -ATPases. Therefore, we discovered that PM H+ -ATPases counteract instead of mediate the auxintriggered rapid H+ -influx, and that TIR1/AFB and TMK1 regulate root growth antagonistically. This opposite effect of TIR1/AFB and TMK1 is consistent during auxin-induced hypocotyl elongation, leading us to explore the relation of two signaling pathways. Assisted with biochemistry and fluorescent imaging, we verified for the first time that TIR1/AFB and TMK1 can interact with each other. The ability of TIR1/AFB binding to membrane lipid provides a basis for the interaction of plasma membrane- and cytosol-localized proteins. Besides, transgenic analysis combined with genetic engineering and biochemistry showed that vi they do function in the same pathway. Particularly, auxin-induced TMK1 increase is TIR1/AFB dependent, suggesting TIR1/AFB regulation on TMK1. Conversely, TMK1 also regulates TIR1/AFB protein levels and thus auxin canonical signaling. To follow the study of rapid growth regulation, we analyzed another rapid growth regulator, signaling peptide RALF1. We showed that RALF1 also triggers a rapid and reversible growth inhibition caused by H + influx, highly resembling but not dependent on auxin. Besides, RALF1 promotes auxin biosynthesis by increasing expression of auxin biosynthesis enzyme YUCCAs and thus induces auxin signaling in ca. 1 hour, contributing to the sustained RALF1-triggered growth inhibition. These studies collectively contribute to understanding rapid regulation on plant cell growth, novel auxin signaling pathway as well as auxin-peptide crosstalk. AU - Li, Lanxin ID - 10083 SN - 2663-337X TI - Rapid cell growth regulation in Arabidopsis ER - TY - JOUR AB - Auxin plays a dual role in growth regulation and, depending on the tissue and concentration of the hormone, it can either promote or inhibit division and expansion processes in plants. Recent studies have revealed that, beyond transcriptional reprogramming, alternative auxincontrolled mechanisms regulate root growth. Here, we explored the impact of different concentrations of the synthetic auxin NAA that establish growth-promoting and -repressing conditions on the root tip proteome and phosphoproteome, generating a unique resource. From the phosphoproteome data, we pinpointed (novel) growth regulators, such as the RALF34-THE1 module. Our results, together with previously published studies, suggest that auxin, H+-ATPases, cell wall modifications and cell wall sensing receptor-like kinases are tightly embedded in a pathway regulating cell elongation. Furthermore, our study assigned a novel role to MKK2 as a regulator of primary root growth and a (potential) regulator of auxin biosynthesis and signalling, and suggests the importance of the MKK2 Thr31 phosphorylation site for growth regulation in the Arabidopsis root tip. AU - Nikonorova, N AU - Murphy, E AU - Fonseca de Lima, CF AU - Zhu, S AU - van de Cotte, B AU - Vu, LD AU - Balcerowicz, D AU - Li, Lanxin AU - Kong, X AU - De Rop, G AU - Beeckman, T AU - Friml, Jiří AU - Vissenberg, K AU - Morris, PC AU - Ding, Z AU - De Smet, I ID - 10015 JF - Cells KW - primary root KW - (phospho)proteomics KW - auxin KW - (receptor) kinase SN - 2073-4409 TI - The Arabidopsis root tip (phospho)proteomes at growth-promoting versus growth-repressing conditions reveal novel root growth regulators VL - 10 ER - TY - GEN AB - Growth regulation tailors plant development to its environment. A showcase is response to gravity, where shoots bend up and roots down1. This paradox is based on opposite effects of the phytohormone auxin, which promotes cell expansion in shoots, while inhibiting it in roots via a yet unknown cellular mechanism2. Here, by combining microfluidics, live imaging, genetic engineering and phospho-proteomics in Arabidopsis thaliana, we advance our understanding how auxin inhibits root growth. We show that auxin activates two distinct, antagonistically acting signalling pathways that converge on the rapid regulation of the apoplastic pH, a causative growth determinant. Cell surface-based TRANSMEMBRANE KINASE1 (TMK1) interacts with and mediates phosphorylation and activation of plasma membrane H+-ATPases for apoplast acidification, while intracellular canonical auxin signalling promotes net cellular H+-influx, causing apoplast alkalinisation. The simultaneous activation of these two counteracting mechanisms poises the root for a rapid, fine-tuned growth modulation while navigating complex soil environment. AU - Li, Lanxin AU - Verstraeten, Inge AU - Roosjen, Mark AU - Takahashi, Koji AU - Rodriguez Solovey, Lesia AU - Merrin, Jack AU - Chen, Jian AU - Shabala, Lana AU - Smet, Wouter AU - Ren, Hong AU - Vanneste, Steffen AU - Shabala, Sergey AU - De Rybel, Bert AU - Weijers, Dolf AU - Kinoshita, Toshinori AU - Gray, William M. AU - Friml, Jiří ID - 10095 SN - 2693-5015 T2 - Research Square TI - Cell surface and intracellular auxin signalling for H+-fluxes in root growth ER - TY - GEN AB - Plasmodesmata (PD) are crucial structures for intercellular communication in multicellular plants with remorins being their crucial plant-specific structural and functional constituents. The PD biogenesis is an intriguing but poorly understood process. By expressing an Arabidopsis remorin protein in mammalian cells, we have reconstituted a PD-like filamentous structure, termed remorin filament (RF), connecting neighboring cells physically and physiologically. Notably, RFs are capable of transporting macromolecules intercellularly, in a way similar to plant PD. With further super-resolution microscopic analysis and biochemical characterization, we found that RFs are also composed of actin filaments, forming the core skeleton structure, aligned with the remorin protein. This unique heterologous filamentous structure might explain the molecular mechanism for remorin function as well as PD construction. Furthermore, remorin protein exhibits a specific distribution manner in the plasma membrane in mammalian cells, representing a lipid nanodomain, depending on its lipid modification status. Our studies not only provide crucial insights into the mechanism of PD biogenesis, but also uncovers unsuspected fundamental mechanistic and evolutionary links between intercellular communication systems of plants and animals. AU - Wei, Zhuang AU - Tan, Shutang AU - Liu, Tao AU - Wu, Yuan AU - Lei, Ji-Gang AU - Chen, ZhengJun AU - Friml, Jiří AU - Xue, Hong-Wei AU - Liao, Kan ID - 7601 T2 - bioRxiv TI - Plasmodesmata-like intercellular connections by plant remorin in animal cells ER - TY - JOUR AU - Zhang, Yuzhou AU - Friml, Jiří ID - 6997 IS - 3 JF - New Phytologist SN - 0028-646x TI - Auxin guides roots to avoid obstacles during gravitropic growth VL - 225 ER - TY - JOUR AB - Plant root architecture dynamically adapts to various environmental conditions, such as salt‐containing soil. The phytohormone abscisic acid (ABA) is involved among others also in these developmental adaptations, but the underlying molecular mechanism remains elusive. Here, a novel branch of the ABA signaling pathway in Arabidopsis involving PYR/PYL/RCAR (abbreviated as PYLs) receptor‐protein phosphatase 2A (PP2A) complex that acts in parallel to the canonical PYLs‐protein phosphatase 2C (PP2C) mechanism is identified. The PYLs‐PP2A signaling modulates root gravitropism and lateral root formation through regulating phytohormone auxin transport. In optimal conditions, PYLs ABA receptor interacts with the catalytic subunits of PP2A, increasing their phosphatase activity and thus counteracting PINOID (PID) kinase‐mediated phosphorylation of PIN‐FORMED (PIN) auxin transporters. By contrast, in salt and osmotic stress conditions, ABA binds to PYLs, inhibiting the PP2A activity, which leads to increased PIN phosphorylation and consequently modulated directional auxin transport leading to adapted root architecture. This work reveals an adaptive mechanism that may flexibly adjust plant root growth to withstand saline and osmotic stresses. It occurs via the cross‐talk between the stress hormone ABA and the versatile developmental regulator auxin. AU - Li, Yang AU - Wang, Yaping AU - Tan, Shutang AU - Li, Zhen AU - Yuan, Zhi AU - Glanc, Matous AU - Domjan, David AU - Wang, Kai AU - Xuan, Wei AU - Guo, Yan AU - Gong, Zhizhong AU - Friml, Jiří AU - Zhang, Jing ID - 7204 IS - 3 JF - Advanced Science TI - Root growth adaptation is mediated by PYLs ABA receptor-PP2A protein phosphatase complex VL - 7 ER - TY - JOUR AB - The phytohormone auxin acts as an amazingly versatile coordinator of plant growth and development. With its morphogen-like properties, auxin controls sites and timing of differentiation and/or growth responses both, in quantitative and qualitative terms. Specificity in the auxin response depends largely on distinct modes of signal transmission, by which individual cells perceive and convert auxin signals into a remarkable diversity of responses. The best understood, or so-called canonical mechanism of auxin perception ultimately results in variable adjustments of the cellular transcriptome, via a short, nuclear signal transduction pathway. Additional findings that accumulated over decades implied that an additional, presumably, cell surface-based auxin perception mechanism mediates very rapid cellular responses and decisively contributes to the cell's overall hormonal response. Recent investigations into both, nuclear and cell surface auxin signalling challenged this assumed partition of roles for different auxin signalling pathways and revealed an unexpected complexity in transcriptional and non-transcriptional cellular responses mediated by auxin. AU - Gallei, Michelle C AU - Luschnig, Christian AU - Friml, Jiří ID - 7142 IS - 2 JF - Current Opinion in Plant Biology SN - 1369-5266 TI - Auxin signalling in growth: Schrödinger's cat out of the bag VL - 53 ER - TY - JOUR AB - Root system architecture (RSA), governed by the phytohormone auxin, endows plants with an adaptive advantage in particular environments. Using geographically representative arabidopsis (Arabidopsis thaliana) accessions as a resource for GWA mapping, Waidmann et al. and Ogura et al. recently identified two novel components involved in modulating auxin-mediated RSA and conferring plant fitness in particular habitats. AU - Xiao, Guanghui AU - Zhang, Yuzhou ID - 7219 IS - 2 JF - Trends in Plant Science SN - 13601385 TI - Adaptive growth: Shaping auxin-mediated root system architecture VL - 25 ER - TY - JOUR AB - The flexible development of plants is characterized by a high capacity for post-embryonic organ formation and tissue regeneration, processes, which require tightly regulated intercellular communication and coordinated tissue (re-)polarization. The phytohormone auxin, the main driver for these processes, is able to establish polarized auxin transport channels, which are characterized by the expression and polar, subcellular localization of the PIN1 auxin transport proteins. These channels are demarcating the position of future vascular strands necessary for organ formation and tissue regeneration. Major progress has been made in the last years to understand how PINs can change their polarity in different contexts and thus guide auxin flow through the plant. However, it still remains elusive how auxin mediates the establishment of auxin conducting channels and the formation of vascular tissue and which cellular processes are involved. By the means of sophisticated regeneration experiments combined with local auxin applications in Arabidopsis thaliana inflorescence stems we show that (i) PIN subcellular dynamics, (ii) PIN internalization by clathrin-mediated trafficking and (iii) an intact actin cytoskeleton required for post-endocytic trafficking are indispensable for auxin channel formation, de novo vascular formation and vascular regeneration after wounding. These observations provide novel insights into cellular mechanism of coordinated tissue polarization during auxin canalization. AU - Mazur, Ewa AU - Gallei, Michelle C AU - Adamowski, Maciek AU - Han, Huibin AU - Robert, Hélène S. AU - Friml, Jiří ID - 7465 IS - 4 JF - Plant Science SN - 01689452 TI - Clathrin-mediated trafficking and PIN trafficking are required for auxin canalization and vascular tissue formation in Arabidopsis VL - 293 ER - TY - JOUR AB - In plants, clathrin mediated endocytosis (CME) represents the major route for cargo internalisation from the cell surface. It has been assumed to operate in an evolutionary conserved manner as in yeast and animals. Here we report characterisation of ultrastructure, dynamics and mechanisms of plant CME as allowed by our advancement in electron microscopy and quantitative live imaging techniques. Arabidopsis CME appears to follow the constant curvature model and the bona fide CME population generates vesicles of a predominantly hexagonal-basket type; larger and with faster kinetics than in other models. Contrary to the existing paradigm, actin is dispensable for CME events at the plasma membrane but plays a unique role in collecting endocytic vesicles, sorting of internalised cargos and directional endosome movement that itself actively promote CME events. Internalized vesicles display a strongly delayed and sequential uncoating. These unique features highlight the independent evolution of the plant CME mechanism during the autonomous rise of multicellularity in eukaryotes. AU - Narasimhan, Madhumitha AU - Johnson, Alexander J AU - Prizak, Roshan AU - Kaufmann, Walter AU - Tan, Shutang AU - Casillas Perez, Barbara E AU - Friml, Jiří ID - 7490 JF - eLife TI - Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants VL - 9 ER - TY - JOUR AB - Endophytic fungi can be beneficial to plant growth. However, the molecular mechanisms underlying colonization of Acremonium spp. remain unclear. In this study, a novel endophytic Acremonium strain was isolated from the buds of Panax notoginseng and named Acremonium sp. D212. The Acremonium sp. D212 could colonize the roots of P. notoginseng, enhance the resistance of P. notoginseng to root rot disease, and promote root growth and saponin biosynthesis in P. notoginseng. Acremonium sp. D212 could secrete indole‐3‐acetic acid (IAA) and jasmonic acid (JA), and inoculation with the fungus increased the endogenous levels of IAA and JA in P. notoginseng. Colonization of the Acremonium sp. D212 in the roots of the rice line Nipponbare was dependent on the concentration of methyl jasmonate (MeJA) (2 to 15 μM) and 1‐naphthalenacetic acid (NAA) (10 to 20 μM). Moreover, the roots of the JA signalling‐defective coi1‐18 mutant were colonized by Acremonium sp. D212 to a lesser degree than those of the wild‐type Nipponbare and miR393b‐overexpressing lines, and the colonization was rescued by MeJA but not by NAA. It suggests that the cross‐talk between JA signalling and the auxin biosynthetic pathway plays a crucial role in the colonization of Acremonium sp. D212 in host plants. AU - Han, L AU - Zhou, X AU - Zhao, Y AU - Zhu, S AU - Wu, L AU - He, Y AU - Ping, X AU - Lu, X AU - Huang, W AU - Qian, J AU - Zhang, L AU - Jiang, X AU - Zhu, D AU - Luo, C AU - Li, S AU - Dong, Q AU - Fu, Q AU - Deng, K AU - Wang, X AU - Wang, L AU - Peng, S AU - Wu, J AU - Li, W AU - Friml, Jiří AU - Zhu, Y AU - He, X AU - Du, Y ID - 7497 IS - 9 JF - Journal of Integrative Plant Biology SN - 1672-9072 TI - Colonization of endophyte Acremonium sp. D212 in Panax notoginseng and rice mediated by auxin and jasmonic acid VL - 62 ER - TY - JOUR AB - In vitro propagation of the ornamentally interesting species Wikstroemia gemmata is limited by the recalcitrance to form adventitious roots. In this article, two strategies to improve the rooting capacity of in vitro microcuttings are presented. Firstly, the effect of exogenous auxin was evaluated in both light and dark cultivated stem segments and also the sucrose-content of the medium was varied in order to determine better rooting conditions. Secondly, different spectral lights were evaluated and the effect on shoot growth and root induction demonstrated that the exact spectral composition of light is important for successful in vitro growth and development of Wikstroemia gemmata. We show that exogenous auxin cannot compensate for the poor rooting under unfavorable light conditions. Adapting the culture conditions is therefore paramount for successful industrial propagation of Wikstroemia gemmata. AU - Verstraeten, Inge AU - Buyle, H. AU - Werbrouck, S. AU - Van Labeke, M.C. AU - Geelen, D. ID - 7540 IS - 1-2 JF - Israel Journal of Plant Sciences SN - 0792-9978 TI - In vitro shoot growth and adventitious rooting of Wikstroemia gemmata depends on light quality VL - 67 ER - TY - JOUR AB - Small RNAs (smRNA, 19–25 nucleotides long), which are transcribed by RNA polymerase II, regulate the expression of genes involved in a multitude of processes in eukaryotes. miRNA biogenesis and the proteins involved in the biogenesis pathway differ across plant and animal lineages. The major proteins constituting the biogenesis pathway, namely, the Dicers (DCL/DCR) and Argonautes (AGOs), have been extensively studied. However, the accessory proteins (DAWDLE (DDL), SERRATE (SE), and TOUGH (TGH)) of the pathway that differs across the two lineages remain largely uncharacterized. We present the first detailed report on the molecular evolution and divergence of these proteins across eukaryotes. Although DDL is present in eukaryotes and prokaryotes, SE and TGH appear to be specific to eukaryotes. The addition/deletion of specific domains and/or domain-specific sequence divergence in the three proteins points to the observed functional divergence of these proteins across the two lineages, which correlates with the differences in miRNA length across the two lineages. Our data enhance the current understanding of the structure–function relationship of these proteins and reveals previous unexplored crucial residues in the three proteins that can be used as a basis for further functional characterization. The data presented here on the number of miRNAs in crown eukaryotic lineages are consistent with the notion of the expansion of the number of miRNA-coding genes in animal and plant lineages correlating with organismal complexity. Whether this difference in functionally correlates with the diversification (or presence/absence) of the three proteins studied here or the miRNA signaling in the plant and animal lineages is unclear. Based on our results of the three proteins studied here and previously available data concerning the evolution of miRNA genes in the plant and animal lineages, we believe that miRNAs probably evolved once in the ancestor to crown eukaryotes and have diversified independently in the eukaryotes. AU - Moturu, Taraka Ramji AU - Sinha, Sansrity AU - Salava, Hymavathi AU - Thula, Sravankumar AU - Nodzyński, Tomasz AU - Vařeková, Radka Svobodová AU - Friml, Jiří AU - Simon, Sibu ID - 7582 IS - 3 JF - Plants TI - Molecular evolution and diversification of proteins involved in miRNA maturation pathway VL - 9 ER - TY - JOUR AB - Directional intercellular transport of the phytohormone auxin mediated by PIN FORMED (PIN) efflux carriers plays essential roles in both coordinating patterning processes and integrating multiple external cues by rapidly redirecting auxin fluxes. Multilevel regulations of PIN activity under internal and external cues are complicated; however, the underlying molecular mechanism remains elusive. Here we demonstrate that 3’-Phosphoinositide-Dependent Protein Kinase1 (PDK1), which is conserved in plants and mammals, functions as a molecular hub integrating the upstream lipid signalling and the downstream substrate activity through phosphorylation. Genetic analysis uncovers that loss-of-function Arabidopsis mutant pdk1.1 pdk1.2 exhibits a plethora of abnormalities in organogenesis and growth, due to the defective PIN-dependent auxin transport. Further cellular and biochemical analyses reveal that PDK1 phosphorylates D6 Protein Kinase to facilitate its activity towards PIN proteins. Our studies establish a lipid-dependent phosphorylation cascade connecting membrane composition-based cellular signalling with plant growth and patterning by regulating morphogenetic auxin fluxes. AU - Tan, Shutang AU - Zhang, Xixi AU - Kong, Wei AU - Yang, Xiao-Li AU - Molnar, Gergely AU - Vondráková, Zuzana AU - Filepová, Roberta AU - Petrášek, Jan AU - Friml, Jiří AU - Xue, Hong-Wei ID - 7600 JF - Nature Plants TI - The lipid code-dependent phosphoswitch PDK1–D6PK activates PIN-mediated auxin efflux in Arabidopsis VL - 6 ER - TY - JOUR AB - In plant cells, environmental stressors promote changes in connectivity between the cortical ER and the PM. Although this process is tightly regulated in space and time, the molecular signals and structural components mediating these changes in inter-organelle communication are only starting to be characterized. In this report, we confirm the presence of a putative tethering complex containing the synaptotagmins 1 and 5 (SYT1 and SYT5) and the Ca2+ and lipid binding protein 1 (CLB1/SYT7). This complex is enriched at ER-PM contact sites (EPCS), have slow responses to changes in extracellular Ca2+, and display severe cytoskeleton-dependent rearrangements in response to the trivalent lanthanum (La3+) and gadolinium (Gd3+) rare earth elements (REEs). Although REEs are generally used as non-selective cation channel blockers at the PM, here we show that the slow internalization of REEs into the cytosol underlies the activation of the Ca2+/Calmodulin intracellular signaling, the accumulation of phosphatidylinositol-4-phosphate (PI4P) at the PM, and the cytoskeleton-dependent rearrangement of the SYT1/SYT5 EPCS complexes. We propose that the observed EPCS rearrangements act as a slow adaptive response to sustained stress conditions, and that this process involves the accumulation of stress-specific phosphoinositides species at the PM. AU - Lee, E AU - Vila Nova Santana, B AU - Samuels, E AU - Benitez-Fuente, F AU - Corsi, E AU - Botella, MA AU - Perez-Sancho, J AU - Vanneste, S AU - Friml, Jiří AU - Macho, A AU - Alves Azevedo, A AU - Rosado, A ID - 7646 IS - 14 JF - Journal of Experimental Botany SN - 0022-0957 TI - Rare earth elements induce cytoskeleton-dependent and PI4P-associated rearrangement of SYT1/SYT5 ER-PM contact site complexes in Arabidopsis VL - 71 ER - TY - JOUR AB - The agricultural green revolution spectacularly enhanced crop yield and lodging resistance with modified DELLA-mediated gibberellin signaling. However, this was achieved at the expense of reduced nitrogen-use efficiency (NUE). Recently, Wu et al. revealed novel gibberellin signaling that provides a blueprint for improving tillering and NUE in Green Revolution varieties (GRVs). AU - Xue, Huidan AU - Zhang, Yuzhou AU - Xiao, Guanghui ID - 7686 IS - 6 JF - Trends in Plant Science SN - 1360-1385 TI - Neo-gibberellin signaling: Guiding the next generation of the green revolution VL - 25 ER - TY - JOUR AB - Hormonal signalling in animals often involves direct transcription factor-hormone interactions that modulate gene expression. In contrast, plant hormone signalling is most commonly based on de-repression via the degradation of transcriptional repressors. Recently, we uncovered a non-canonical signalling mechanism for the plant hormone auxin whereby auxin directly affects the activity of the atypical auxin response factor (ARF), ETTIN towards target genes without the requirement for protein degradation. Here we show that ETTIN directly binds auxin, leading to dissociation from co-repressor proteins of the TOPLESS/TOPLESS-RELATED family followed by histone acetylation and induction of gene expression. This mechanism is reminiscent of animal hormone signalling as it affects the activity towards regulation of target genes and provides the first example of a DNA-bound hormone receptor in plants. Whilst auxin affects canonical ARFs indirectly by facilitating degradation of Aux/IAA repressors, direct ETTIN-auxin interactions allow switching between repressive and de-repressive chromatin states in an instantly-reversible manner. AU - Kuhn, André AU - Ramans Harborough, Sigurd AU - McLaughlin, Heather M AU - Natarajan, Bhavani AU - Verstraeten, Inge AU - Friml, Jiří AU - Kepinski, Stefan AU - Østergaard, Lars ID - 7793 JF - eLife SN - 2050-084X TI - Direct ETTIN-auxin interaction controls chromatin states in gynoecium development VL - 9 ER - TY - JOUR AB - Directional transport of the phytohormone auxin is a versatile, plant-specific mechanism regulating many aspects of plant development. The recently identified plant hormones, strigolactones (SLs), are implicated in many plant traits; among others, they modify the phenotypic output of PIN-FORMED (PIN) auxin transporters for fine-tuning of growth and developmental responses. Here, we show in pea and Arabidopsis that SLs target processes dependent on the canalization of auxin flow, which involves auxin feedback on PIN subcellular distribution. D14 receptor- and MAX2 F-box-mediated SL signaling inhibits the formation of auxin-conducting channels after wounding or from artificial auxin sources, during vasculature de novo formation and regeneration. At the cellular level, SLs interfere with auxin effects on PIN polar targeting, constitutive PIN trafficking as well as clathrin-mediated endocytosis. Our results identify a non-transcriptional mechanism of SL action, uncoupling auxin feedback on PIN polarity and trafficking, thereby regulating vascular tissue formation and regeneration. AU - Zhang, J AU - Mazur, E AU - Balla, J AU - Gallei, Michelle C AU - Kalousek, P AU - Medveďová, Z AU - Li, Y AU - Wang, Y AU - Prat, Tomas AU - Vasileva, Mina K AU - Reinöhl, V AU - Procházka, S AU - Halouzka, R AU - Tarkowski, P AU - Luschnig, C AU - Brewer, PB AU - Friml, Jiří ID - 8138 IS - 1 JF - Nature Communications SN - 2041-1723 TI - Strigolactones inhibit auxin feedback on PIN-dependent auxin transport canalization VL - 11 ER - TY - JOUR AU - He, Peng AU - Zhang, Yuzhou AU - Xiao, Guanghui ID - 8271 IS - 9 JF - Molecular Plant SN - 16742052 TI - Origin of a subgenome and genome evolution of allotetraploid cotton species VL - 13 ER - TY - JOUR AB - Cytokinins are mobile multifunctional plant hormones with roles in development and stress resilience. Although their Histidine Kinase receptors are substantially localised to the endoplasmic reticulum, cellular sites of cytokinin perception and importance of spatially heterogeneous cytokinin distribution continue to be debated. Here we show that cytokinin perception by plasma membrane receptors is an effective additional path for cytokinin response. Readout from a Two Component Signalling cytokinin-specific reporter (TCSn::GFP) closely matches intracellular cytokinin content in roots, yet we also find cytokinins in extracellular fluid, potentially enabling action at the cell surface. Cytokinins covalently linked to beads that could not pass the plasma membrane increased expression of both TCSn::GFP and Cytokinin Response Factors. Super-resolution microscopy of GFP-labelled receptors and diminished TCSn::GFP response to immobilised cytokinins in cytokinin receptor mutants, further indicate that receptors can function at the cell surface. We argue that dual intracellular and surface locations may augment flexibility of cytokinin responses. AU - Antoniadi, Ioanna AU - Novák, Ondřej AU - Gelová, Zuzana AU - Johnson, Alexander J AU - Plíhal, Ondřej AU - Simerský, Radim AU - Mik, Václav AU - Vain, Thomas AU - Mateo-Bonmatí, Eduardo AU - Karady, Michal AU - Pernisová, Markéta AU - Plačková, Lenka AU - Opassathian, Korawit AU - Hejátko, Jan AU - Robert, Stéphanie AU - Friml, Jiří AU - Doležal, Karel AU - Ljung, Karin AU - Turnbull, Colin ID - 8337 JF - Nature Communications TI - Cell-surface receptors enable perception of extracellular cytokinins VL - 11 ER - TY - JOUR AB - Spontaneously arising channels that transport the phytohormone auxin provide positional cues for self-organizing aspects of plant development such as flexible vasculature regeneration or its patterning during leaf venation. The auxin canalization hypothesis proposes a feedback between auxin signaling and transport as the underlying mechanism, but molecular players await discovery. We identified part of the machinery that routes auxin transport. The auxin-regulated receptor CAMEL (Canalization-related Auxin-regulated Malectin-type RLK) together with CANAR (Canalization-related Receptor-like kinase) interact with and phosphorylate PIN auxin transporters. camel and canar mutants are impaired in PIN1 subcellular trafficking and auxin-mediated PIN polarization, which macroscopically manifests as defects in leaf venation and vasculature regeneration after wounding. The CAMEL-CANAR receptor complex is part of the auxin feedback that coordinates polarization of individual cells during auxin canalization. AU - Hajny, Jakub AU - Prat, Tomas AU - Rydza, N AU - Rodriguez Solovey, Lesia AU - Tan, Shutang AU - Verstraeten, Inge AU - Domjan, David AU - Mazur, E AU - Smakowska-Luzan, E AU - Smet, W AU - Mor, E AU - Nolf, J AU - Yang, B AU - Grunewald, W AU - Molnar, Gergely AU - Belkhadir, Y AU - De Rybel, B AU - Friml, Jiří ID - 8721 IS - 6516 JF - Science SN - 0036-8075 TI - Receptor kinase module targets PIN-dependent auxin transport during canalization VL - 370 ER - TY - JOUR AB - Peptides derived from non-functional precursors play important roles in various developmental processes, but also in (a)biotic stress signaling. Our (phospho)proteome-wide analyses of C-terminally encoded peptide 5 (CEP5)-mediated changes revealed an impact on abiotic stress-related processes. Drought has a dramatic impact on plant growth, development and reproduction, and the plant hormone auxin plays a role in drought responses. Our genetic, physiological, biochemical and pharmacological results demonstrated that CEP5-mediated signaling is relevant for osmotic and drought stress tolerance in Arabidopsis, and that CEP5 specifically counteracts auxin effects. Specifically, we found that CEP5 signaling stabilizes AUX/IAA transcriptional repressors, suggesting the existence of a novel peptide-dependent control mechanism that tunes auxin signaling. These observations align with the recently described role of AUX/IAAs in stress tolerance and provide a novel role for CEP5 in osmotic and drought stress tolerance. AU - Smith, S AU - Zhu, S AU - Joos, L AU - Roberts, I AU - Nikonorova, N AU - Vu, LD AU - Stes, E AU - Cho, H AU - Larrieu, A AU - Xuan, W AU - Goodall, B AU - van de Cotte, B AU - Waite, JM AU - Rigal, A AU - R Harborough, SR AU - Persiau, G AU - Vanneste, S AU - Kirschner, GK AU - Vandermarliere, E AU - Martens, L AU - Stahl, Y AU - Audenaert, D AU - Friml, Jiří AU - Felix, G AU - Simon, R AU - Bennett, M AU - Bishopp, A AU - De Jaeger, G AU - Ljung, K AU - Kepinski, S AU - Robert, S AU - Nemhauser, J AU - Hwang, I AU - Gevaert, K AU - Beeckman, T AU - De Smet, I ID - 7949 IS - 8 JF - Molecular & Cellular Proteomics TI - The CEP5 peptide promotes abiotic stress tolerance, as revealed by quantitative proteomics, and attenuates the AUX/IAA equilibrium in Arabidopsis VL - 19 ER - TY - JOUR AB - Cell polarity is a fundamental feature of all multicellular organisms. In plants, prominent cell polarity markers are PIN auxin transporters crucial for plant development. To identify novel components involved in cell polarity establishment and maintenance, we carried out a forward genetic screening with PIN2:PIN1-HA;pin2 Arabidopsis plants, which ectopically express predominantly basally localized PIN1 in the root epidermal cells leading to agravitropic root growth. From the screen, we identified the regulator of PIN polarity 12 (repp12) mutation, which restored gravitropic root growth and caused PIN1-HA polarity switch from basal to apical side of root epidermal cells. Complementation experiments established the repp12 causative mutation as an amino acid substitution in Aminophospholipid ATPase3 (ALA3), a phospholipid flippase with predicted function in vesicle formation. ala3 T-DNA mutants show defects in many auxin-regulated processes, in asymmetric auxin distribution and in PIN trafficking. Analysis of quintuple and sextuple mutants confirmed a crucial role of ALA proteins in regulating plant development and in PIN trafficking and polarity. Genetic and physical interaction studies revealed that ALA3 functions together with GNOM and BIG3 ARF GEFs. Taken together, our results identified ALA3 flippase as an important interactor and regulator of ARF GEF functioning in PIN polarity, trafficking and auxin-mediated development. AU - Zhang, Xixi AU - Adamowski, Maciek AU - Marhavá, Petra AU - Tan, Shutang AU - Zhang, Yuzhou AU - Rodriguez Solovey, Lesia AU - Zwiewka, Marta AU - Pukyšová, Vendula AU - Sánchez, Adrià Sans AU - Raxwal, Vivek Kumar AU - Hardtke, Christian S. AU - Nodzynski, Tomasz AU - Friml, Jiří ID - 7619 IS - 5 JF - The Plant Cell SN - 1040-4651 TI - Arabidopsis flippases cooperate with ARF GTPase exchange factors to regulate the trafficking and polarity of PIN auxin transporters VL - 32 ER - TY - JOUR AB - Clathrin-mediated endocytosis (CME) and its core endocytic machinery are evolutionarily conserved across all eukaryotes. In mammals, the heterotetrameric adaptor protein complex-2 (AP-2) sorts plasma membrane (PM) cargoes into vesicles through the recognition of motifs based on tyrosine or di-leucine in their cytoplasmic tails. However, in plants, very little is known on how PM proteins are sorted for CME and whether similar motifs are required. In Arabidopsis thaliana, the brassinosteroid (BR) receptor, BR INSENSITIVE1 (BRI1), undergoes endocytosis that depends on clathrin and AP-2. Here we demonstrate that BRI1 binds directly to the medium AP-2 subunit, AP2M. The cytoplasmic domain of BRI1 contains five putative canonical surface-exposed tyrosine-based endocytic motifs. The tyrosine-to-phenylalanine substitution in Y898KAI reduced BRI1 internalization without affecting its kinase activity. Consistently, plants carrying the BRI1Y898F mutation were hypersensitive to BRs. Our study demonstrates that AP-2-dependent internalization of PM proteins via the recognition of functional tyrosine motifs also operates in plants. AU - Liu, D AU - Kumar, R AU - LAN, Claus AU - Johnson, Alexander J AU - Siao, W AU - Vanhoutte, I AU - Wang, P AU - Bender, KW AU - Yperman, K AU - Martins, S AU - Zhao, X AU - Vert, G AU - Van Damme, D AU - Friml, Jiří AU - Russinova, E ID - 8607 IS - 11 JF - Plant Cell SN - 1040-4651 TI - Endocytosis of BRASSINOSTEROID INSENSITIVE1 is partly driven by a canonical tyrosine-based Motif VL - 32 ER - TY - JOUR AB - The TPLATE complex (TPC) is a key endocytic adaptor protein complex in plants. TPC in Arabidopsis (Arabidopsis thaliana) contains six evolutionarily conserved subunits and two plant-specific subunits, AtEH1/Pan1 and AtEH2/Pan1, although cytoplasmic proteins are not associated with the hexameric subcomplex in the cytoplasm. To investigate the dynamic assembly of the octameric TPC at the plasma membrane (PM), we performed state-of-the-art dual-color live cell imaging at physiological and lowered temperatures. Lowering the temperature slowed down endocytosis, thereby enhancing the temporal resolution of the differential recruitment of endocytic components. Under both normal and lowered temperature conditions, the core TPC subunit TPLATE and the AtEH/Pan1 proteins exhibited simultaneous recruitment at the PM. These results, together with co-localization analysis of different TPC subunits, allow us to conclude that TPC in plant cells is not recruited to the PM sequentially but as an octameric complex. AU - Wang, J AU - Mylle, E AU - Johnson, Alexander J AU - Besbrugge, N AU - De Jaeger, G AU - Friml, Jiří AU - Pleskot, R AU - van Damme, D ID - 7695 IS - 3 JF - Plant Physiology SN - 0032-0889 TI - High temporal resolution reveals simultaneous plasma membrane recruitment of TPLATE complex subunits VL - 183 ER - TY - JOUR AB - * Morphogenesis and adaptive tropic growth in plants depend on gradients of the phytohormone auxin, mediated by the membrane‐based PIN‐FORMED (PIN) auxin transporters. PINs localize to a particular side of the plasma membrane (PM) or to the endoplasmic reticulum (ER) to directionally transport auxin and maintain intercellular and intracellular auxin homeostasis, respectively. However, the molecular cues that confer their diverse cellular localizations remain largely unknown. * In this study, we systematically swapped the domains between ER‐ and PM‐localized PIN proteins, as well as between apical and basal PM‐localized PINs from Arabidopsis thaliana , to shed light on why PIN family members with similar topological structures reside at different membrane compartments within cells. * Our results show that not only do the N‐ and C‐terminal transmembrane domains (TMDs) and central hydrophilic loop contribute to their differential subcellular localizations and cellular polarity, but that the pairwise‐matched N‐ and C‐terminal TMDs resulting from intramolecular domain–domain coevolution are also crucial for their divergent patterns of localization. * These findings illustrate the complexity of the evolutionary path of PIN proteins in acquiring their plethora of developmental functions and adaptive growth in plants. AU - Zhang, Yuzhou AU - Hartinger, Corinna AU - Wang, Xiaojuan AU - Friml, Jiří ID - 7697 IS - 5 JF - New Phytologist SN - 0028-646X TI - Directional auxin fluxes in plants by intramolecular domain‐domain co‐evolution of PIN auxin transporters VL - 227 ER - TY - JOUR AB - Previously, we reported that the allelic de-etiolated by zinc (dez) and trichome birefringence (tbr) mutants exhibit photomorphogenic development in the dark, which is enhanced by high Zn. TRICHOME BIREFRINGENCE-LIKE proteins had been implicated in transferring acetyl groups to various hemicelluloses. Pectin O-acetylation levels were lower in dark-grown dez seedlings than in the wild type. We observed Zn-enhanced photomorphogenesis in the dark also in the reduced wall acetylation 2 (rwa2-3) mutant, which exhibits lowered O-acetylation levels of cell wall macromolecules including pectins and xyloglucans, supporting a role for cell wall macromolecule O-acetylation in the photomorphogenic phenotypes of rwa2-3 and dez. Application of very short oligogalacturonides (vsOGs) restored skotomorphogenesis in dark-grown dez and rwa2-3. Here we demonstrate that in dez, O-acetylation of non-pectin cell wall components, notably of xyloglucan, is enhanced. Our results highlight the complexity of cell wall homeostasis and indicate against an influence of xyloglucan O-acetylation on light-dependent seedling development. AU - Sinclair, Scott A AU - Gille, S. AU - Pauly, M. AU - Krämer, U. ID - 7417 IS - 1 JF - Plant Signaling & Behavior SN - 1559-2324 TI - Regulation of acetylation of plant cell wall components is complex and responds to external stimuli VL - 15 ER - TY - THES AB - The plant hormone auxin plays indispensable roles in plant growth and development. An essential level of regulation in auxin action is the directional auxin transport within cells. The establishment of auxin gradient in plant tissue has been attributed to local auxin biosynthesis and directional intercellular auxin transport, which both are controlled by various environmental and developmental signals. It is well established that asymmetric auxin distribution in cells is achieved by polarly localized PIN-FORMED (PIN) auxin efflux transporters. Despite the initial insights into cellular mechanisms of PIN polarization obtained from the last decades, the molecular mechanism and specific regulators mediating PIN polarization remains elusive. In this thesis, we aim to find novel players in PIN subcellular polarity regulation during Arabidopsis development. We first characterize the physiological effect of piperonylic acid (PA) on Arabidopsis hypocotyl gravitropic bending and PIN polarization. Secondly, we reveal the importance of SCFTIR1/AFB auxin signaling pathway in shoot gravitropism bending termination. In addition, we also explore the role of myosin XI complex, and actin cytoskeleton in auxin feedback regulation on PIN polarity. In Chapter 1, we give an overview of the current knowledge about PIN-mediated auxin fluxes in various plant tropic responses. In Chapter 2, we study the physiological effect of PA on shoot gravitropic bending. Our results show that PA treatment inhibits auxin-mediated PIN3 repolarization by interfering with PINOID and PIN3 phosphorylation status, ultimately leading to hyperbending hypocotyls. In Chapter 3, we provide evidence to show that the SCFTIR1/AFB nuclear auxin signaling pathway is crucial and required for auxin-mediated PIN3 repolarization and shoot gravitropic bending termination. In Chapter 4, we perform a phosphoproteomics approach and identify the motor protein Myosin XI and its binding protein, the MadB2 family, as an essential regulator of PIN polarity for auxin-canalization related developmental processes. In Chapter 5, we demonstrate the vital role of actin cytoskeleton in auxin feedback on PIN polarity by regulating PIN subcellular trafficking. Overall, the data presented in this PhD thesis brings novel insights into the PIN polar localization regulation that resulted in the (re)establishment of the polar auxin flow and gradient in response to environmental stimuli during plant development. AU - Han, Huibin ID - 8589 SN - 2663-337X TI - Novel insights into PIN polarity regulation during Arabidopsis development ER - TY - JOUR AU - Han, Huibin AU - Rakusova, Hana AU - Verstraeten, Inge AU - Zhang, Yuzhou AU - Friml, Jiří ID - 7643 IS - 5 JF - Plant Physiology SN - 0032-0889 TI - SCF TIR1/AFB auxin signaling for bending termination during shoot gravitropism VL - 183 ER - TY - JOUR AB - Earlier, we demonstrated that transcript levels of METAL TOLERANCE PROTEIN2 (MTP2) and of HEAVY METAL ATPase2 (HMA2) increase strongly in roots of Arabidopsis upon prolonged zinc (Zn) deficiency and respond to shoot physiological Zn status, and not to the local Zn status in roots. This provided evidence for shoot-to-root communication in the acclimation of plants to Zn deficiency. Zn-deficient soils limit both the yield and quality of agricultural crops and can result in clinically relevant nutritional Zn deficiency in human populations. Implementing Zn deficiency during cultivation of the model plant Arabidopsis thaliana on agar-solidified media is difficult because trace element contaminations are present in almost all commercially available agars. Here, we demonstrate root morphological acclimations to Zn deficiency on agar-solidified medium following the effective removal of contaminants. These advancements allow reproducible phenotyping toward understanding fundamental plant responses to deficiencies of Zn and other essential trace elements. AU - Sinclair, Scott A AU - Krämer, U. ID - 7416 IS - 1 JF - Plant Signaling & Behavior SN - 1559-2324 TI - Generation of effective zinc-deficient agar-solidified media allows identification of root morphology changes in response to zinc limitation VL - 15 ER - TY - JOUR AB - The widely used non-steroidal anti-inflammatory drugs (NSAIDs) are derivatives of the phytohormone salicylic acid (SA). SA is well known to regulate plant immunity and development, whereas there have been few reports focusing on the effects of NSAIDs in plants. Our studies here reveal that NSAIDs exhibit largely overlapping physiological activities to SA in the model plant Arabidopsis. NSAID treatments lead to shorter and agravitropic primary roots and inhibited lateral root organogenesis. Notably, in addition to the SA-like action, which in roots involves binding to the protein phosphatase 2A (PP2A), NSAIDs also exhibit PP2A-independent effects. Cell biological and biochemical analyses reveal that many NSAIDs bind directly to and inhibit the chaperone activity of TWISTED DWARF1, thereby regulating actin cytoskeleton dynamics and subsequent endosomal trafficking. Our findings uncover an unexpected bioactivity of human pharmaceuticals in plants and provide insights into the molecular mechanism underlying the cellular action of this class of anti-inflammatory compounds. AU - Tan, Shutang AU - Di Donato, Martin AU - Glanc, Matous AU - Zhang, Xixi AU - Klíma, Petr AU - Liu, Jie AU - Bailly, Aurélien AU - Ferro, Noel AU - Petrášek, Jan AU - Geisler, Markus AU - Friml, Jiří ID - 8943 IS - 9 JF - Cell Reports TI - Non-steroidal anti-inflammatory drugs target TWISTED DWARF1-regulated actin dynamics and auxin transport-mediated plant development VL - 33 ER - TY - JOUR AB - Wound healing in plant tissues, consisting of rigid cell wall-encapsulated cells, represents a considerable challenge and occurs through largely unknown mechanisms distinct from those in animals. Owing to their inability to migrate, plant cells rely on targeted cell division and expansion to regenerate wounds. Strict coordination of these wound-induced responses is essential to ensure efficient, spatially restricted wound healing. Single-cell tracking by live imaging allowed us to gain mechanistic insight into the wound perception and coordination of wound responses after laser-based wounding in Arabidopsis root. We revealed a crucial contribution of the collapse of damaged cells in wound perception and detected an auxin increase specific to cells immediately adjacent to the wound. This localized auxin increase balances wound-induced cell expansion and restorative division rates in a dose-dependent manner, leading to tumorous overproliferation when the canonical TIR1 auxin signaling is disrupted. Auxin and wound-induced turgor pressure changes together also spatially define the activation of key components of regeneration, such as the transcription regulator ERF115. Our observations suggest that the wound signaling involves the sensing of collapse of damaged cells and a local auxin signaling activation to coordinate the downstream transcriptional responses in the immediate wound vicinity. AU - Hörmayer, Lukas AU - Montesinos López, Juan C AU - Marhavá, Petra AU - Benková, Eva AU - Yoshida, Saiko AU - Friml, Jiří ID - 8002 IS - 26 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Wounding-induced changes in cellular pressure and localized auxin signalling spatially coordinate restorative divisions in roots VL - 117 ER - TY - JOUR AB - Plants, like other multicellular organisms, survive through a delicate balance between growth and defense against pathogens. Salicylic acid (SA) is a major defense signal in plants, and the perception mechanism as well as downstream signaling activating the immune response are known. Here, we identify a parallel SA signaling that mediates growth attenuation. SA directly binds to A subunits of protein phosphatase 2A (PP2A), inhibiting activity of this complex. Among PP2A targets, the PIN2 auxin transporter is hyperphosphorylated in response to SA, leading to changed activity of this important growth regulator. Accordingly, auxin transport and auxin-mediated root development, including growth, gravitropic response, and lateral root organogenesis, are inhibited. This study reveals how SA, besides activating immunity, concomitantly attenuates growth through crosstalk with the auxin distribution network. Further analysis of this dual role of SA and characterization of additional SA-regulated PP2A targets will provide further insights into mechanisms maintaining a balance between growth and defense. AU - Tan, Shutang AU - Abas, Melinda F AU - Verstraeten, Inge AU - Glanc, Matous AU - Molnar, Gergely AU - Hajny, Jakub AU - Lasák, Pavel AU - Petřík, Ivan AU - Russinova, Eugenia AU - Petrášek, Jan AU - Novák, Ondřej AU - Pospíšil, Jiří AU - Friml, Jiří ID - 7427 IS - 3 JF - Current Biology SN - 09609822 TI - Salicylic acid targets protein phosphatase 2A to attenuate growth in plants VL - 30 ER - TY - JOUR AB - Plant survival depends on vascular tissues, which originate in a self‐organizing manner as strands of cells co‐directionally transporting the plant hormone auxin. The latter phenomenon (also known as auxin canalization) is classically hypothesized to be regulated by auxin itself via the effect of this hormone on the polarity of its own intercellular transport. Correlative observations supported this concept, but molecular insights remain limited. In the current study, we established an experimental system based on the model Arabidopsis thaliana, which exhibits auxin transport channels and formation of vasculature strands in response to local auxin application. Our methodology permits the genetic analysis of auxin canalization under controllable experimental conditions. By utilizing this opportunity, we confirmed the dependence of auxin canalization on a PIN‐dependent auxin transport and nuclear, TIR1/AFB‐mediated auxin signaling. We also show that leaf venation and auxin‐mediated PIN repolarization in the root require TIR1/AFB signaling. Further studies based on this experimental system are likely to yield better understanding of the mechanisms underlying auxin transport polarization in other developmental contexts. AU - Mazur, E AU - Kulik, Ivan AU - Hajny, Jakub AU - Friml, Jiří ID - 7500 IS - 5 JF - New Phytologist SN - 0028-646x TI - Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis VL - 226 ER -