@article{22956, abstract = {Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet how such heterogeneities are integrated with the mechanochemical state of the tissue and stabilized at the chromatin level into stable, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (YAP1). We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable and self-organized tissue architecture.}, author = {Schwayer, Cornelia and Barbiero, Silvia and Brückner, David and Oost, Koen C. and Baader, Clara and Repina, Nicole A. and Kim, Jinse and Diaz, Oscar E. and Uccelli, Isa and Capolupo, Laura and Meylan, Ludivine Challet and Kalck, Veronique and Moos, Franziska and Suppinger, Simon and Yang, Qiutan and Schnabl, Jakob and Kilik, Umut and Bourdon, Matthieu and Camp, J. Gray and Stockinger, Brigitta and Ferrari, Alessandra and Bühler, Marc and Stadler, Michael B. and Hannezo, Edouard B and Liberali, Prisca}, issn = {1097-4172}, journal = {Cell}, keywords = {tissue patterning, heterogeneity, mechanics, intestinal regeneration, epigenetic competence, multiscale integration, modeling, organoids, image-based phenotyping, Yap1}, number = {17}, pages = {5266--5282.e17}, publisher = {Cell Press}, title = {{Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning}}, doi = {10.1016/j.cell.2026.06.009}, volume = {189}, year = {2026}, } @article{22144, abstract = {Most cells polarize and migrate in response to electrical fields. In this issue of Cell, Belliveau et al. identify TMEM154/Galvanin, a receptor that serves as a cellular antenna to sense electrical gradients and guide migration toward the cathode.}, author = {Riedl, Michael and Sixt, Michael K}, issn = {1097-4172}, journal = {Cell}, number = {13}, pages = {3845--3846}, publisher = {Cell Press}, title = {{A new sense for electrical fields}}, doi = {10.1016/j.cell.2026.05.038}, volume = {189}, year = {2026}, } @article{22955, abstract = {The regulation of 3D cell shape is a fundamental problem of life. In multicellular tissues, cell shape emerges through the balance of forces inside and outside the cell. In epithelia, the basement membrane (BM) is the first extracellular barrier that cells sense biochemically and mechanically. Despite this, little is known about how BM mechanical properties are regulated and how they impact cell shape. Through mathematical modeling, we show that the stress relaxation time of the BM can regulate cell shape. Using molecular dynamics simulations, we show that the stress relaxation time of a collagen IV network can be inferred from the lifetime of collagen IV molecules. To measure collagen IV lifetime in vivo, we develop a fluorescent timer reporter for collagen IV and show that perlecan modifies collagen IV lifetime. This cross-disciplinary approach establishes a multiscale framework to probe matrix turnover, and its regulation and function in cell shape control.}, author = {Barrientos, Ricardo and Meadowcroft, Billie and Sánchez-Sánchez, Besaiz J. and Stramer, Brian M. and Paluch, Ewa K. and Charras, Guillaume and Banerjee, Shiladitya and Šarić, Anđela and Mao, Yanlan}, issn = {1097-4172}, journal = {Cell}, number = {18}, pages = {5611--5624.e4}, publisher = {Cell Press}, title = {{Basement membrane turnover controls cell shape}}, doi = {10.1016/j.cell.2026.07.010}, volume = {189}, year = {2026}, } @article{18879, abstract = {Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ. }, author = {Watson, Jake and Vargas Barroso, Victor M and Morse, Rebecca and Navas Olivé, Andrea C and Tavakoli, Mojtaba and Danzl, Johann G and Tomschik, Matthias and Rössler, Karl and Jonas, Peter M}, issn = {1097-4172}, journal = {Cell}, number = {2}, pages = {501--514.e18}, publisher = {Cell Press}, title = {{Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory}}, doi = {10.1016/j.cell.2024.11.022}, volume = {188}, year = {2025}, } @article{19602, abstract = {N4-methylcytosine (4mC) is an important DNA modification in prokaryotes, but its relevance and even its presence in eukaryotes have been mysterious. Here we show that spermatogenesis in the liverwort Marchantia polymorpha involves two waves of extensive DNA methylation reprogramming. First, 5-methylcytosine (5mC) expands from transposons to the entire genome. Notably, the second wave installs 4mC throughout genic regions, covering over 50% of CG sites in sperm. 4mC requires a methyltransferase (MpDN4MT1a) that is specifically expressed during late spermiogenesis. Deletion of MpDN4MT1a alters the sperm transcriptome, causes sperm swimming and fertility defects, and impairs post-fertilization development. Our results reveal extensive 4mC in a eukaryote, identify a family of eukaryotic methyltransferases, and elucidate the biological functions of 4mC in reproductive development, thereby expanding the repertoire of functional eukaryotic DNA modifications.}, author = {Walker, James and Zhang, Jingyi and Liu, Yalin and Xu, Shujuan and Yu, Yiming and Vickers, Martin and Ouyang, Weizhi and Tálas, Judit and Dolan, Liam and Nakajima, Keiji and Feng, Xiaoqi}, issn = {1097-4172}, journal = {Cell}, number = {11}, pages = {2890--2906.e14}, publisher = {Cell Press}, title = {{Extensive N4 cytosine methylation is essential for Marchantia sperm function}}, doi = {10.1016/j.cell.2025.03.014}, volume = {188}, year = {2025}, } @article{20143, abstract = {Bacteria and archaea deploy diverse antiviral defense systems, many of which remain mechanistically uncharacterized. Here, we characterize Kiwa, a widespread two-component system composed of the transmembrane sensor KwaA and the DNA-binding effector KwaB. Cryogenic electron microscopy (cryo-EM) analysis reveals that KwaA and KwaB assemble into a large, membrane-associated supercomplex. Upon phage binding, KwaA senses infection at the membrane, leading to KwaB binding of ejected phage DNA and inhibition of replication and late transcription, without inducing host cell death. Although KwaB can bind DNA independently, its antiviral activity requires association with KwaA, suggesting spatial or conformational regulation. We show that the phage-encoded DNA-mimic protein Gam directly binds and inhibits KwaB but that co-expression with the Gam-targeted RecBCD system restores protection by Kiwa. Our findings support a model in which Kiwa coordinates membrane-associated detection of phage infection with downstream DNA binding by its effector, forming a spatially coordinated antiviral mechanism.}, author = {Zhang, Zhiying and Todeschini, Thomas C. and Wu, Yi and Kogay, Roman and Naji, Ameena and Cardenas Rodriguez, Joaquin and Mondi, Rupavidhya and Kaganovich, Daniel and Taylor, David W. and Bravo, Jack Peter Kelly and Teplova, Marianna and Amen, Triana and Koonin, Eugene and Patel, Dinshaw J. and Nobrega, Franklin L.}, issn = {1097-4172}, journal = {Cell}, number = {21}, pages = {5862--5877.e23}, publisher = {Cell Press}, title = {{Kiwa is a membrane-embedded defense supercomplex activated at phage attachment sites}}, doi = {10.1016/j.cell.2025.07.002}, volume = {188}, year = {2025}, } @article{14826, abstract = {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.}, author = {Kuhn, Andre and Roosjen, Mark and Mutte, Sumanth and Dubey, Shiv Mani and Carrillo Carrasco, Vanessa Polet and Boeren, Sjef and Monzer, Aline and Koehorst, Jasper and Kohchi, Takayuki and Nishihama, Ryuichi and Fendrych, Matyas and Sprakel, Joris and Friml, Jiří and Weijers, Dolf}, issn = {1097-4172}, journal = {Cell}, keywords = {General Biochemistry, Genetics and Molecular Biology}, number = {1}, pages = {130--148.e17}, publisher = {Elsevier}, title = {{RAF-like protein kinases mediate a deeply conserved, rapid auxin response}}, doi = {10.1016/j.cell.2023.11.021}, volume = {187}, year = {2024}, } @article{10825, abstract = {In development, lineage segregation is coordinated in time and space. An important example is the mammalian inner cell mass, in which the primitive endoderm (PrE, founder of the yolk sac) physically segregates from the epiblast (EPI, founder of the fetus). While the molecular requirements have been well studied, the physical mechanisms determining spatial segregation between EPI and PrE remain elusive. Here, we investigate the mechanical basis of EPI and PrE sorting. We find that rather than the differences in static cell surface mechanical parameters as in classical sorting models, it is the differences in surface fluctuations that robustly ensure physical lineage sorting. These differential surface fluctuations systematically correlate with differential cellular fluidity, which we propose together constitute a non-equilibrium sorting mechanism for EPI and PrE lineages. By combining experiments and modeling, we identify cell surface dynamics as a key factor orchestrating the correct spatial segregation of the founder embryonic lineages.}, author = {Yanagida, Ayaka and Corujo-Simon, Elena and Revell, Christopher K. and Sahu, Preeti and Stirparo, Giuliano G. and Aspalter, Irene M. and Winkel, Alex K. and Peters, Ruby and De Belly, Henry and Cassani, Davide A.D. and Achouri, Sarra and Blumenfeld, Raphael and Franze, Kristian and Hannezo, Edouard B and Paluch, Ewa K. and Nichols, Jennifer and Chalut, Kevin J.}, issn = {1097-4172}, journal = {Cell}, number = {5}, pages = {777--793.e20}, publisher = {Cell Press}, title = {{Cell surface fluctuations regulate early embryonic lineage sorting}}, doi = {10.1016/j.cell.2022.01.022}, volume = {185}, year = {2022}, } @article{10573, abstract = {How tissues acquire complex shapes is a fundamental question in biology and regenerative medicine. Zebrafish semicircular canals form from invaginations in the otic epithelium (buds) that extend and fuse to form the hubs of each canal. We find that conventional actomyosin-driven behaviors are not required. Instead, local secretion of hyaluronan, made by the enzymes uridine 5′-diphosphate dehydrogenase (ugdh) and hyaluronan synthase 3 (has3), drives canal morphogenesis. Charged hyaluronate polymers osmotically swell with water and generate isotropic extracellular pressure to deform the overlying epithelium into buds. The mechanical anisotropy needed to shape buds into tubes is conferred by a polarized distribution of actomyosin and E-cadherin-rich membrane tethers, which we term cytocinches. Most work on tissue morphogenesis ascribes actomyosin contractility as the driving force, while the extracellular matrix shapes tissues through differential stiffness. Our work inverts this expectation. Hyaluronate pressure shaped by anisotropic tissue stiffness may be a widespread mechanism for powering morphological change in organogenesis and tissue engineering.}, author = {Munjal, Akankshi and Hannezo, Edouard B and Tsai, Tony Y.C. and Mitchison, Timothy J. and Megason, Sean G.}, issn = {1097-4172}, journal = {Cell}, number = {26}, pages = {6313--6325.e18}, publisher = {Elsevier}, title = {{Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis}}, doi = {10.1016/j.cell.2021.11.025}, volume = {184}, year = {2021}, } @article{9316, abstract = {Embryo morphogenesis is impacted by dynamic changes in tissue material properties, which have been proposed to occur via processes akin to phase transitions (PTs). Here, we show that rigidity percolation provides a simple and robust theoretical framework to predict material/structural PTs of embryonic tissues from local cell connectivity. By using percolation theory, combined with directly monitoring dynamic changes in tissue rheology and cell contact mechanics, we demonstrate that the zebrafish blastoderm undergoes a genuine rigidity PT, brought about by a small reduction in adhesion-dependent cell connectivity below a critical value. We quantitatively predict and experimentally verify hallmarks of PTs, including power-law exponents and associated discontinuities of macroscopic observables. Finally, we show that this uniform PT depends on blastoderm cells undergoing meta-synchronous divisions causing random and, consequently, uniform changes in cell connectivity. Collectively, our theoretical and experimental findings reveal the structural basis of material PTs in an organismal context.}, author = {Petridou, Nicoletta and Corominas-Murtra, Bernat and Heisenberg, Carl-Philipp J and Hannezo, Edouard B}, issn = {1097-4172}, journal = {Cell}, number = {7}, pages = {1914--1928.e19}, publisher = {Elsevier}, title = {{Rigidity percolation uncovers a structural basis for embryonic tissue phase transitions}}, doi = {10.1016/j.cell.2021.02.017}, volume = {184}, year = {2021}, } @article{7789, abstract = {During embryonic and postnatal development, organs and tissues grow steadily to achieve their final size at the end of puberty. However, little is known about the cellular dynamics that mediate postnatal growth. By combining in vivo clonal lineage tracing, proliferation kinetics, single-cell transcriptomics, andin vitro micro-pattern experiments, we resolved the cellular dynamics taking place during postnatal skin epidermis expansion. Our data revealed that harmonious growth is engineered by a single population of developmental progenitors presenting a fixed fate imbalance of self-renewing divisions with an ever-decreasing proliferation rate. Single-cell RNA sequencing revealed that epidermal developmental progenitors form a more uniform population compared with adult stem and progenitor cells. Finally, we found that the spatial pattern of cell division orientation is dictated locally by the underlying collagen fiber orientation. Our results uncover a simple design principle of organ growth where progenitors and differentiated cells expand in harmony with their surrounding tissues.}, author = {Dekoninck, Sophie and Hannezo, Edouard B and Sifrim, Alejandro and Miroshnikova, Yekaterina A. and Aragona, Mariaceleste and Malfait, Milan and Gargouri, Souhir and De Neunheuser, Charlotte and Dubois, Christine and Voet, Thierry and Wickström, Sara A. and Simons, Benjamin D. and Blanpain, Cédric}, issn = {1097-4172}, journal = {Cell}, number = {3}, pages = {604--620.e22}, publisher = {Elsevier}, title = {{Defining the design principles of skin epidermis postnatal growth}}, doi = {10.1016/j.cell.2020.03.015}, volume = {181}, year = {2020}, } @article{6508, abstract = {Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally. Using biophysical experimentation and theory, we show that ooplasm pulling is mediated by bulk actin network flows exerting friction forces on the ooplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. Our study defines a novel role of cell-cycle-controlled bulk actin polymerization waves in oocyte polarization via ooplasmic segregation.}, author = {Shamipour, Shayan and Kardos, Roland and Xue, Shi-lei and Hof, Björn and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {1097-4172}, journal = {Cell}, number = {6}, pages = {1463--1479.e18}, publisher = {Elsevier}, title = {{Bulk actin dynamics drive phase segregation in zebrafish oocytes}}, doi = {10.1016/j.cell.2019.04.030}, volume = {177}, year = {2019}, } @article{7001, author = {Schwayer, Cornelia and Shamipour, Shayan and Pranjic-Ferscha, Kornelija and Schauer, Alexandra and Balda, M and Tada, M and Matter, K and Heisenberg, Carl-Philipp J}, issn = {1097-4172}, journal = {Cell}, number = {4}, pages = {937--952.e18}, publisher = {Cell Press}, title = {{Mechanosensation of tight junctions depends on ZO-1 phase separation and flow}}, doi = {10.1016/j.cell.2019.10.006}, volume = {179}, year = {2019}, } @article{6877, author = {Kopf, Aglaja and Sixt, Michael K}, issn = {1097-4172}, journal = {Cell}, number = {1}, pages = {51--53}, publisher = {Elsevier}, title = {{The neural crest pitches in to remove apoptotic debris}}, doi = {10.1016/j.cell.2019.08.047}, volume = {179}, year = {2019}, } @article{6351, abstract = {A process of restorative patterning in plant roots correctly replaces eliminated cells to heal local injuries despite the absence of cell migration, which underpins wound healing in animals. Patterning in plants relies on oriented cell divisions and acquisition of specific cell identities. Plants regularly endure wounds caused by abiotic or biotic environmental stimuli and have developed extraordinary abilities to restore their tissues after injuries. Here, we provide insight into a mechanism of restorative patterning that repairs tissues after wounding. Laser-assisted elimination of different cells in Arabidopsis root combined with live-imaging tracking during vertical growth allowed analysis of the regeneration processes in vivo. Specifically, the cells adjacent to the inner side of the injury re-activated their stem cell transcriptional programs. They accelerated their progression through cell cycle, coordinately changed the cell division orientation, and ultimately acquired de novo the correct cell fates to replace missing cells. These observations highlight existence of unknown intercellular positional signaling and demonstrate the capability of specified cells to re-acquire stem cell programs as a crucial part of the plant-specific mechanism of wound healing.}, author = {Marhavá, Petra and Hörmayer, Lukas and Yoshida, Saiko and Marhavy, Peter and Benková, Eva and Friml, Jiří}, issn = {1097-4172}, journal = {Cell}, number = {4}, pages = {957--969.e13}, publisher = {Elsevier}, title = {{Re-activation of stem cell pathways for pattern restoration in plant wound healing}}, doi = {10.1016/j.cell.2019.04.015}, volume = {177}, year = {2019}, } @article{9458, abstract = {Dnmt1 epigenetically propagates symmetrical CG methylation in many eukaryotes. Their genomes are typically depleted of CG dinucleotides because of imperfect repair of deaminated methylcytosines. Here, we extensively survey diverse species lacking Dnmt1 and show that, surprisingly, symmetrical CG methylation is nonetheless frequently present and catalyzed by a different DNA methyltransferase family, Dnmt5. Numerous Dnmt5-containing organisms that diverged more than a billion years ago exhibit clustered methylation, specifically in nucleosome linkers. Clustered methylation occurs at unprecedented densities and directly disfavors nucleosomes, contributing to nucleosome positioning between clusters. Dense methylation is enabled by a regime of genomic sequence evolution that enriches CG dinucleotides and drives the highest CG frequencies known. Species with linker methylation have small, transcriptionally active nuclei that approach the physical limits of chromatin compaction. These features constitute a previously unappreciated genome architecture, in which dense methylation influences nucleosome positions, likely facilitating nuclear processes under extreme spatial constraints.}, author = {Huff, Jason T. and Zilberman, Daniel}, issn = {1097-4172}, journal = {Cell}, number = {6}, pages = {1286--1297}, publisher = {Elsevier}, title = {{Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes}}, doi = {10.1016/j.cell.2014.01.029}, volume = {156}, year = {2014}, } @article{9459, abstract = {Nucleosome remodelers of the DDM1/Lsh family are required for DNA methylation of transposable elements, but the reason for this is unknown. How DDM1 interacts with other methylation pathways, such as small-RNA-directed DNA methylation (RdDM), which is thought to mediate plant asymmetric methylation through DRM enzymes, is also unclear. Here, we show that most asymmetric methylation is facilitated by DDM1 and mediated by the methyltransferase CMT2 separately from RdDM. We find that heterochromatic sequences preferentially require DDM1 for DNA methylation and that this preference depends on linker histone H1. RdDM is instead inhibited by heterochromatin and absolutely requires the nucleosome remodeler DRD1. Together, DDM1 and RdDM mediate nearly all transposon methylation and collaborate to repress transposition and regulate the methylation and expression of genes. Our results indicate that DDM1 provides DNA methyltransferases access to H1-containing heterochromatin to allow stable silencing of transposable elements in cooperation with the RdDM pathway.}, author = {Zemach, Assaf and Kim, M. Yvonne and Hsieh, Ping-Hung and Coleman-Derr, Devin and Eshed-Williams, Leor and Thao, Ka and Harmer, Stacey L. and Zilberman, Daniel}, issn = {1097-4172}, journal = {Cell}, number = {1}, pages = {193--205}, publisher = {Elsevier}, title = {{The Arabidopsis nucleosome remodeler DDM1 allows DNA methyltransferases to access H1-containing heterochromatin}}, doi = {10.1016/j.cell.2013.02.033}, volume = {153}, year = {2013}, } @article{2996, abstract = {Plants, compared to animals, exhibit an amazing adaptability and plasticity in their development. This is largely dependent on the ability of plants to form new organs, such as lateral roots, leaves, and flowers during postembryonic development. Organ primordia develop from founder cell populations into organs by coordinated cell division and differentiation. Here, we show that organ formation in Arabidopsis involves dynamic gradients of the signaling molecule auxin with maxima at the primordia tips. These gradients are mediated by cellular efflux requiring asymmetrically localized PIN proteins, which represent a functionally redundant network for auxin distribution in both aerial and underground organs. PIN1 polar localization undergoes a dynamic rearrangement, which correlates with establishment of auxin gradients and primordium development. Our results suggest that PIN-dependent, local auxin gradients represent a common module for formation of all plant organs, regardless of their mature morphology or developmental origin. }, author = {Benková, Eva and Michniewicz, Marta and Sauer, Michael and Teichmann, Thomas and Seifertová, Daniela and Jürgens, Gerd and Friml, Jirí}, issn = {1097-4172}, journal = {Cell}, number = {5}, pages = {591 -- 602}, publisher = {Cell Press}, title = {{Local, efflux-dependent auxin gradients as a common module for plant organ formation}}, doi = {10.1016/S0092-8674(03)00924-3}, volume = {115}, year = {2003}, }