@article{21744, abstract = {The paraventricular hypothalamus (PVH) controls behavioral and physiologic processes, including appetite, social behavior, autonomic outflow, and pituitary hormone secretion. However, molecular markers for centrally projecting PVH neuron populations remain largely undefined, and a complete census of PVH cell types has not been established. Therefore, we performed extensive single-cell/nucleus RNA sequencing to catalog PVH neuron subtypes and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to map them spatially. Our spatial transcriptomic atlas resolves 26 Sim1+ and 29 GABAergic neuron populations from the PVH and surrounding areas. Additionally, projection-based profiling identified neurons that project to the parabrachial region (PB) and spinal cord, helping to determine PVH populations that regulate satiety and sympathetic nervous system activity, respectively. Notably, activation of PB-projecting PVH neurons expressing Brs3 reduces food intake, and silencing them causes obesity. Together, this atlas contributes high-resolution PVH spatial and circuit-based gene expression profiles, representing a valuable resource for the field of homeostasis.}, author = {Li, Yuxi and Butler, Trevor C. and Nardone, Stefano and Jacobs, Christopher L. and Douglass, Amelia May Barnett and Madara, Joseph C. and McDonough, Miriam C. and Tao, Jenkang and Lowenstein, Elijah D. and Wang, Luhong and Pant, Deepti and Walker, Samuel J. and Wang, Annette and Srinivasan, Harini and Yang, Zongfang and Campbell, John N. and Tsai, Linus T. and Lowell, Bradford B. and Resch, Jon M.}, issn = {2211-1247}, journal = {Cell Reports}, number = {2}, publisher = {Elsevier}, title = {{A spatial and projection-based transcriptomic atlas of paraventricular hypothalamic cell types}}, doi = {10.1016/j.celrep.2025.116904}, volume = {45}, year = {2026}, } @article{21746, abstract = {As vertebrates transitioned from water to land, locomotion shifted from undulatory swimming to limb-based movement. How spinal circuits and their cell types evolved to support this transition remains unclear. We leverage frog metamorphosis, which recapitulates this transition within a single organism, to define how spinal circuits generate aquatic versus terrestrial motor patterns. At swim stages, spinal architecture is uniform, with a transcriptionally and anatomically homogeneous motor and interneurons. As limbs develop and their movement complexifies, spinal circuits expand in neuron number and subtype diversity. This expansion is most pronounced for V1 inhibitory neurons, which increase ∼70-fold and diversify into transcriptionally distinct subtypes. Disrupting transcription factors defining emerging motor and V1 populations reveals molecular segregation between swim and limb circuits, highlighting the role of subtype diversity in motor coordination. A multifold increase in inhibitory neuron diversity thus underlies the tail-to-limb locomotor transition, providing a framework for spinal circuit adaptation during vertebrate evolution.}, author = {Vijatovic, David and Toma, Florina Alexandra and Ignatyev, Y and Harrington, Zoe P and Sommer, Christoph M and Hauschild, Robert and Smits, Matthijs Geert and Dalla Vecchia, Marco and Trevisan, Alexandra J. and Chapman, Phillip and Julseth, Mara and Brenner-Morton, Susan and Gabitto, Mariano I. and Dasen, Jeremy S. and Bikoff, Jay B. and Sweeney, Lora Beatrice Jaeger}, issn = {2211-1247}, journal = {Cell Reports}, number = {4}, publisher = {Elsevier}, title = {{Multifold increase in spinal inhibitory cell types with emergence of limb movement}}, doi = {10.1016/j.celrep.2026.117227}, volume = {45}, year = {2026}, } @article{19404, abstract = {Cell migration is a fundamental process during embryonic development. Most studies in vivo have focused on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal-pole-directed migration of LME cells, while the ectoderm at the animal pole halts it. These differences in permissiveness depend on the lateral ectoderm being more cohesive than the animal ectoderm, a property controlled by bone morphogenetic protein (BMP) signaling within the ectoderm. Collectively, these findings identify ectoderm tissue cohesion as one critical factor in regulating LME migration during zebrafish gastrulation.}, author = {Tavano, Ste and Brückner, David and Tasciyan, Saren and Tong, Xin and Kardos, Roland and Schauer, Alexandra and Hauschild, Robert and Heisenberg, Carl-Philipp J}, issn = {2211-1247}, journal = {Cell Reports}, number = {3}, publisher = {Elsevier}, title = {{BMP-dependent patterning of ectoderm tissue material properties modulates lateral mesendoderm cell migration during early zebrafish gastrulation}}, doi = {10.1016/j.celrep.2025.115387}, volume = {44}, year = {2025}, } @article{20029, abstract = {Vacuolar acidification is crucial for the homeostasis of intracellular pH and the recycling of proteins and nutrients in cells, thereby playing important roles in various physiological processes related to vacuolar function. The key factors regulating vacuolar acidification and underlying mechanisms remain unclear. Here, we report that Arabidopsis phospholipase Dζ2 (PLDζ2) promotes the acidification of the vacuolar lumen to stimulate autophagic degradation under phosphorus deficiency. The pldζ2 mutant massively accumulates autophagic structures while exhibiting premature leaf senescence under nutrient starvation. Impaired autophagic flux, lytic vacuole morphology, and lytic degradation in pldζ2 indicate that PLDζ2 regulates autophagy by affecting the vacuolar function. PLDζ2 locates in both tonoplast and cytoplasm. Genetic, structural, and biochemical studies demonstrate that PLDζ2 directly interacts with vacuolar-type ATPase (V-ATPase) subunit D (VATD) to promote vacuolar acidification and autophagy under phosphorus starvation. These findings reveal the importance of V-ATPase and vacuolar pH in autophagic activity and provide clues in elucidating the regulatory mechanism of vacuolar acidification.}, author = {Guan, Bin and Xie, Ke Xuan and Du, Xin Qiao and Bai, Yu Xuan and Hao, Peng Chao and Lin, Wen Hui and Friml, Jiří and Xue, Hong Wei}, issn = {2211-1247}, journal = {Cell Reports}, number = {7}, publisher = {Elsevier}, title = {{Arabidopsis phospholipase Dζ2 facilitates vacuolar acidification and autophagy under phosphorus starvation by interacting with VATD}}, doi = {10.1016/j.celrep.2025.116024}, volume = {44}, year = {2025}, } @article{20099, abstract = {The hippocampus, critical for learning and memory, is dogmatically described as a trisynaptic circuit where dentate gyrus granule cells (GCs), CA3 pyramidal neurons (PNs), and CA1 PNs are serially connected. However, CA3 also forms an autoassociative network, and its PNs have diverse morphologies, intrinsic properties, and GC input levels. How PN subtypes compose this recurrent network is unknown. To determine the synaptic arrangement of identified CA3 PNs, we combine multicellular patch-clamp recording and post hoc morphological analysis in mouse hippocampal slices. PNs can be divided into distinct “superficial” and “deep” subclasses, the latter including previously reported “athorny” cells. Subclasses have distinct input-output transformations and asymmetric connectivity, which is more abundant from superficial to deep PNs, splitting CA3 locally into two parallel recurrent networks. Coincident spontaneous inhibition occurs frequently within but not between subclasses, implying subclass-specific inhibitory innervation. Our results suggest two separately controlled sublayers for parallel information processing in hippocampal CA3.}, author = {Watson, Jake and Vargas Barroso, Victor M and Jonas, Peter M}, issn = {2211-1247}, journal = {Cell Reports}, number = {8}, publisher = {Elsevier}, title = {{Cell-specific wiring routes information flow through hippocampal CA3}}, doi = {10.1016/j.celrep.2025.116080}, volume = {44}, year = {2025}, } @article{20116, abstract = {Auxin regulates various aspects of plant growth and development by modulating the transcription of target genes through the degradation of auxin/indole-3-acetic acid (Aux/IAA) repressors via the 26S proteasome. Proteasome regulator 1 (PTRE1), a positive regulator of proteasome activity, has been implicated in auxin-mediated proteasome suppression; however, the mechanism by which auxin modulates PTRE1 function remains unclear. Here, we demonstrate that auxin promotes the interaction between germin-like protein 1 (GLP1) and PTRE1, facilitating PTRE1 retention at the plasma membrane. The relocation of PTRE1 results in reduced nuclear 26S proteasome activity, and thus the attenuated Aux/IAA degradation and altered Aux/IAA homeostasis, ultimately resulting in suppressed auxin-mediated transcriptional regulation. Our findings uncover a previously uncharacterized regulatory axis in auxin signaling that controls Aux/IAA protein stability, functioning alongside the TIR1- and TRANSMEMBRANE KINASE 1 (TMK1)-mediated pathways, and highlight the coordination of auxin signaling from the cell surface to the nucleus via auxin-induced PTRE1 relocation, which fine-tunes Aux/IAA protein homeostasis and auxin responses.}, author = {Xu, Faqing and Yu, Yongqiang and Guan, Bin and Xu, Tongda and Xu, Zhihong and Xue, Hongwei}, issn = {2211-1247}, journal = {Cell Reports}, number = {8}, publisher = {Elsevier}, title = {{Germin-like protein 1 interacts with proteasome regulator 1 to regulate auxin signaling by controlling Aux/IAA homeostasis}}, doi = {10.1016/j.celrep.2025.116056}, volume = {44}, year = {2025}, } @article{15374, abstract = {Clathrin-mediated endocytosis (CME) is an essential process of cargo uptake operating in all eukaryotes. In animals and yeast, BAR-SH3 domain proteins, endophilins and amphiphysins, function at the conclusion of CME to recruit factors for vesicle scission and uncoating. Arabidopsis thaliana contains the BAR-SH3 domain proteins SH3P1–SH3P3, but their role is poorly understood. Here, we identify SH3Ps as functional homologs of endophilin/amphiphysin. SH3P1–SH3P3 bind to discrete foci at the plasma membrane (PM), and SH3P2 recruits late to a subset of clathrin-coated pits. The SH3P2 PM recruitment pattern is nearly identical to its interactor, a putative uncoating factor, AUXILIN-LIKE1. Notably, SH3P1–SH3P3 are required for most of AUXILIN-LIKE1 recruitment to the PM. This indicates a plant-specific modification of CME, where BAR-SH3 proteins recruit auxilin-like uncoating factors rather than the uncoating phosphatases, synaptojanins. SH3P1–SH3P3 act redundantly in overall CME with the plant-specific endocytic adaptor TPLATE complex but not due to an SH3 domain in its TASH3 subunit.}, author = {Adamowski, Maciek and Randuch, Marek and Matijevic, Ivana and Narasimhan, Madhumitha and Friml, Jiří}, issn = {2211-1247}, journal = {Cell Reports}, number = {5}, publisher = {Cell Press}, title = {{SH3Ps recruit auxilin-like vesicle uncoating factors for clathrin-mediated endocytosis}}, doi = {10.1016/j.celrep.2024.114195}, volume = {43}, year = {2024}, } @article{17089, abstract = {How the coordination of neuronal spiking and brain rhythms between hippocampal subregions supports memory function remains elusive. We studied the interregional coordination of CA3 neuronal spiking with CA1 theta oscillations by recording electrophysiological signals along the proximodistal axis of the hippocampus in rats that were performing a high-memory-demand recognition memory task adapted from humans. We found that CA3 population spiking occurs preferentially at the peak of distal CA1 theta oscillations when memory was tested but only when previously encountered stimuli were presented. In addition, decoding analyses revealed that only population cell firing of proximal CA3 together with that of distal CA1 can predict performance at test in the present non-spatial task. Overall, our work demonstrates an important role for the synchronization of CA3 neuronal activity with CA1 theta oscillations during memory testing.}, author = {Ku, Shih Pi and Atucha, Erika and Alavi, Nico and Mulla-Osman, Halla and Kayumova, Rukhshona and Yoshida, Motoharu and Csicsvari, Jozsef L and Sauvage, Magdalena M.}, issn = {2211-1247}, journal = {Cell Reports}, number = {6}, publisher = {Elsevier}, title = {{Phase locking of hippocampal CA3 neurons to distal CA1 theta oscillations selectively predicts memory performance}}, doi = {10.1016/j.celrep.2024.114276}, volume = {43}, year = {2024}, } @article{12672, abstract = {Cytosine methylation within CG dinucleotides (mCG) can be epigenetically inherited over many generations. Such inheritance is thought to be mediated by a semiconservative mechanism that produces binary present/absent methylation patterns. However, we show here that in Arabidopsis thaliana h1ddm1 mutants, intermediate heterochromatic mCG is stably inherited across many generations and is quantitatively associated with transposon expression. We develop a mathematical model that estimates the rates of semiconservative maintenance failure and de novo methylation at each transposon, demonstrating that mCG can be stably inherited at any level via a dynamic balance of these activities. We find that DRM2 – the core methyltransferase of the RNA-directed DNA methylation pathway – catalyzes most of the heterochromatic de novo mCG, with de novo rates orders of magnitude higher than previously thought, whereas chromomethylases make smaller contributions. Our results demonstrate that stable epigenetic inheritance of mCG in plant heterochromatin is enabled by extensive de novo methylation.}, author = {Lyons, David B. and Briffa, Amy and He, Shengbo and Choi, Jaemyung and Hollwey, Elizabeth and Colicchio, Jack and Anderson, Ian and Feng, Xiaoqi and Howard, Martin and Zilberman, Daniel}, issn = {2211-1247}, journal = {Cell Reports}, number = {3}, publisher = {Elsevier}, title = {{Extensive de novo activity stabilizes epigenetic inheritance of CG methylation in Arabidopsis transposons}}, doi = {10.1016/j.celrep.2023.112132}, volume = {42}, year = {2023}, } @article{14314, abstract = {The execution of cognitive functions requires coordinated circuit activity across different brain areas that involves the associated firing of neuronal assemblies. Here, we tested the circuit mechanism behind assembly interactions between the hippocampus and the medial prefrontal cortex (mPFC) of adult rats by recording neuronal populations during a rule-switching task. We identified functionally coupled CA1-mPFC cells that synchronized their activity beyond that expected from common spatial coding or oscillatory firing. When such cell pairs fired together, the mPFC cell strongly phase locked to CA1 theta oscillations and maintained consistent theta firing phases, independent of the theta timing of their CA1 counterpart. These functionally connected CA1-mPFC cells formed interconnected assemblies. While firing together with their CA1 assembly partners, mPFC cells fired along specific theta sequences. Our results suggest that upregulated theta oscillatory firing of mPFC cells can signal transient interactions with specific CA1 assemblies, thus enabling distributed computations.}, author = {Nardin, Michele and Käfer, Karola and Stella, Federico and Csicsvari, Jozsef L}, issn = {2211-1247}, journal = {Cell Reports}, number = {9}, publisher = {Elsevier}, title = {{Theta oscillations as a substrate for medial prefrontal-hippocampal assembly interactions}}, doi = {10.1016/j.celrep.2023.113015}, volume = {42}, year = {2023}, } @article{14402, abstract = {Alpha oscillations are a distinctive feature of the awake resting state of the human brain. However, their functional role in resting-state neuronal dynamics remains poorly understood. Here we show that, during resting wakefulness, alpha oscillations drive an alternation of attenuation and amplification bouts in neural activity. Our analysis indicates that inhibition is activated in pulses that last for a single alpha cycle and gradually suppress neural activity, while excitation is successively enhanced over a few alpha cycles to amplify neural activity. Furthermore, we show that long-term alpha amplitude fluctuations—the “waxing and waning” phenomenon—are an attenuation-amplification mechanism described by a power-law decay of the activity rate in the “waning” phase. Importantly, we do not observe such dynamics during non-rapid eye movement (NREM) sleep with marginal alpha oscillations. The results suggest that alpha oscillations modulate neural activity not only through pulses of inhibition (pulsed inhibition hypothesis) but also by timely enhancement of excitation (or disinhibition).}, author = {Lombardi, Fabrizio and Herrmann, Hans J. and Parrino, Liborio and Plenz, Dietmar and Scarpetta, Silvia and Vaudano, Anna Elisabetta and De Arcangelis, Lucilla and Shriki, Oren}, issn = {2211-1247}, journal = {Cell Reports}, number = {10}, publisher = {Elsevier}, title = {{Beyond pulsed inhibition: Alpha oscillations modulate attenuation and amplification of neural activity in the awake resting state}}, doi = {10.1016/j.celrep.2023.113162}, volume = {42}, year = {2023}, } @article{11143, abstract = {Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a+/− mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a+/− mice at postnatal days (P) 16–21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a+/− mice that did not survive and in Scn1a+/− mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome: combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology.}, author = {Kaneko, Keisuke and Currin, Christopher and Goff, Kevin M. and Wengert, Eric R. and Somarowthu, Ala and Vogels, Tim P and Goldberg, Ethan M.}, issn = {2211-1247}, journal = {Cell Reports}, number = {13}, publisher = {Elsevier}, title = {{Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome}}, doi = {10.1016/j.celrep.2022.110580}, volume = {38}, year = {2022}, } @article{9603, abstract = {Mosaic analysis with double markers (MADM) offers one approach to visualize and concomitantly manipulate genetically defined cells in mice with single-cell resolution. MADM applications include the analysis of lineage, single-cell morphology and physiology, genomic imprinting phenotypes, and dissection of cell-autonomous gene functions in vivo in health and disease. Yet, MADM can only be applied to <25% of all mouse genes on select chromosomes to date. To overcome this limitation, we generate transgenic mice with knocked-in MADM cassettes near the centromeres of all 19 autosomes and validate their use across organs. With this resource, >96% of the entire mouse genome can now be subjected to single-cell genetic mosaic analysis. Beyond a proof of principle, we apply our MADM library to systematically trace sister chromatid segregation in distinct mitotic cell lineages. We find striking chromosome-specific biases in segregation patterns, reflecting a putative mechanism for the asymmetric segregation of genetic determinants in somatic stem cell division.}, author = {Contreras, Ximena and Amberg, Nicole and Davaatseren, Amarbayasgalan and Hansen, Andi H and Sonntag, Johanna and Andersen, Lill and Bernthaler, Tina and Streicher, Carmen and Heger, Anna-Magdalena and Johnson, Randy L. and Schwarz, Lindsay A. and Luo, Liqun and Rülicke, Thomas and Hippenmeyer, Simon}, issn = {2211-1247}, journal = {Cell Reports}, number = {12}, publisher = {Cell Press}, title = {{A genome-wide library of MADM mice for single-cell genetic mosaic analysis}}, doi = {10.1016/j.celrep.2021.109274}, volume = {35}, year = {2021}, } @article{9642, abstract = {Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.}, author = {Venturino, Alessandro and Schulz, Rouven and De Jesús-Cortés, Héctor and Maes, Margaret E and Nagy, Balint and Reilly-Andújar, Francis and Colombo, Gloria and Cubero, Ryan J and Schoot Uiterkamp, Florianne E and Bear, Mark F. and Siegert, Sandra}, issn = {2211-1247}, journal = {Cell Reports}, number = {1}, publisher = {Elsevier}, title = {{Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain}}, doi = {10.1016/j.celrep.2021.109313}, volume = {36}, year = {2021}, } @article{7877, abstract = {The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations inNIPBLaccount for most cases ofthe rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report aMAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus.Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable fornormal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fataloutcome of an out-of-frame single nucleotide duplication inNIPBL, engineered in two different cell lines,alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interactwith MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protectiveagainst out-of-frame mutations that is potentially relevant for other genetic conditions.}, author = {Parenti, Ilaria and Diab, Farah and Gil, Sara Ruiz and Mulugeta, Eskeatnaf and Casa, Valentina and Berutti, Riccardo and Brouwer, Rutger W.W. and Dupé, Valerie and Eckhold, Juliane and Graf, Elisabeth and Puisac, Beatriz and Ramos, Feliciano and Schwarzmayr, Thomas and Gines, Macarena Moronta and Van Staveren, Thomas and Van Ijcken, Wilfred F.J. and Strom, Tim M. and Pié, Juan and Watrin, Erwan and Kaiser, Frank J. and Wendt, Kerstin S.}, issn = {2211-1247}, journal = {Cell Reports}, number = {7}, publisher = {Elsevier}, title = {{MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome}}, doi = {10.1016/j.celrep.2020.107647}, volume = {31}, year = {2020}, } @article{8943, abstract = {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.}, author = {Tan, Shutang and Di Donato, Martin and Glanc, Matous and Zhang, Xixi and Klíma, Petr and Liu, Jie and Bailly, Aurélien and Ferro, Noel and Petrášek, Jan and Geisler, Markus and Friml, Jiří}, issn = {2211-1247}, journal = {Cell Reports}, number = {9}, publisher = {Elsevier}, title = {{Non-steroidal anti-inflammatory drugs target TWISTED DWARF1-regulated actin dynamics and auxin transport-mediated plant development}}, doi = {10.1016/j.celrep.2020.108463}, volume = {33}, year = {2020}, }