bims-ginsta 2026-06-07 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–06–07
34 papers selected by
Jinrong Hu, National University of Singapore

Opposing actomyosin pools establish epithelial polarity during naive pluripotency exit.
Xenophagocytosis blockade enhances interspecies chimerism.
LASER couples damage sensing to ESCRT assembly for lysosome repair.
Deep learning of functional perturbations from condensate morphology.
Hyaluronan Underlies the Emergence of Form, Fate, and Function in Human Cardioids.
Somatic cells compartmentalise their carbohydrate metabolism to sustain germ cell survival.
Asymmetric attrition and secondary chromosome destabilization after double-strand breaks in human embryonic development.
Chromatin architecture sets origin licensing capacity.
Nucleolar Dynamics During Oogenesis.
Kinase condensates enrich ATP and trigger autophosphorylation.
Importin-β1 functions as a chromatin sensor to position the contractile ring for cytokinesis.
Nascent protein retention at polysomes reduces kinetic barriers to self-assembly.
Single-cell mapping of regulatory DNA-protein interactions.
A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
Lipid composition and mechanical force underlie multi-modal regulation of Piezo1 gating.
Mechanisms of germ-soma communication during follicular growth.
Epiblast lumenogenesis is not a mammalian-specific trait.
JCAD couples tight junction condensates to actin and RhoA to maintain the endothelial barrier.
Fibronectin matrix remodelling modulates the active nematic dynamics of cancer-associated fibroblasts.
Adaptive Replication Fork Acceleration by CDK1-Cyclin B1 Sustains Genome Duplication despite Impaired Origin Firing.
Direct Mapping of CDK2 Substrates in Embryonic Stem Cells Uncovers an AP-Site Repair Mechanism via HMCES Phosphorylation.
GPI‑anchored protein nanoclusters license migrasome expansion and serve as exocytic platforms for migrasome.
Rapid actin filament turnover maintains cortical connectivity while allowing for cell cortex deformation and flow.
A progenitor cell population contributes to prenatal injury repair and neonatal antimicrobial defense in the small intestine.
Embryo-scale Visual Cell Sorting reveals a conserved transcriptomic signature of nucleolar size linked to proteostasis.
Simultaneous brain-wide single-cell recording resolves spatiotemporal memory architecture.
Widespread transcriptional memory shapes heritable states and functional heterogeneity in cancer and stem cells.
Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense.
Zebrafish knock-in lines enabling live visualization of extracellular matrix dynamics during development and regeneration.
BMP signaling during gastrulation pre-patterns the dorsal spinal cord.
Segmental specification of the human female fetal reproductive tract revealed by spatiotemporal dynamics.
Tight junction structure, assembly and (dys)function.
Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
Subsarcomeric regulation of thin and thick filaments in skeletal muscle myofibrils.

J Cell Biol. 2026 Aug 03. pii: e202408198. [Epub ahead of print]225(8):

Opposing actomyosin pools establish epithelial polarity during naive pluripotency exit.

Yu Shi, Nadia I Manzi, Nicole R Grater, Nitya Kopparapu, Lauren S Ohler, Bailey N de Jesus, Daniel J Dickinson.

Epithelial cell polarity is fundamental for embryonic development and organ function. During organogenesis, epithelia often develop from unpolarized precursor cells. How mammalian epithelial cells establish polarity de novo is unclear, in part due to challenges of observing this process in real time in nontransformed cells. Here, we leverage 3D spheroid culture of mouse embryonic stem cells, fluorescent protein knock-in, and live imaging to study epithelial polarity establishment. We show that apical myosin activity, regulated by myosin light chain kinase (MLCK), is crucial for proper epithelial polarity in this system. MLCK-dependent actin flows carry ZO-1, a tight junction component, to the apical junction. A second pool of myosin, regulated by Rho kinase, localizes basally and modulates ZO-1 recruitment to the membrane. MLCK inhibition also disrupts localization of atypical protein kinase C and podocalyxin, supporting a broader role of MLCK-dependent myosin in establishing the apical membrane. Our results support a model in which distinct apical and basal actomyosin pools coordinate epithelial polarity establishment.

DOI: https://doi.org/10.1083/jcb.202408198
Cell. 2026 Jun 05. pii: S0092-8674(26)00575-1. [Epub ahead of print]

Xenophagocytosis blockade enhances interspecies chimerism.

Sicong Wang, Kouta Niizuma, Daniel Dan Liu, Fabian P Suchy, Alyssa H Chang, Saman Tabatabaee, Hideyuki Sato, Ayaka Yanagida, Hideki Masaki, Nathan Hidajat, Shota Homma, Masashi Miyauchi, Joydeep Bhadury, Carsten T Charlesworth, Jinyu Zhang, Irving L Weissman, Hiromitsu Nakauchi.

  Organ shortage remains a major challenge in transplantation medicine. Interspecies blastocyst complementation offers a promising strategy to generate human organs in livestock. However, efficient xenogeneic donor cell engraftment remains challenging. Here, we identify an innate immune barrier wherein host macrophages selectively eliminate viable xenogeneic donor cells, a process we term xenophagocytosis. Mechanistically, xenogeneic cells display elevated phosphatidylserine, an "eat-me" signal recognized by host macrophages through phagocytic receptor Axl. We demonstrate three orthogonal strategies for xenophagocytosis blockade: genetic ablation of macrophages or the Axl receptor in the host embryo or overexpression of the "don't-eat-me" signal CD47 or the phosphatidylserine-regulating flippase ATP11C in donor cells. Xenophagocytosis blockade enhances rat and human donor chimerism in mouse embryos and improves interspecies pancreas complementation efficiency. These findings reveal a previously unrecognized innate immune barrier that safeguards species integrity during early embryogenesis and provide mechanistic insights to enhance xenogeneic chimerism for generating human organs in livestock.

Keywords:  blastocyst complementation; developmental quality control; exogenic organogenesis; innate immune response; interspecies chimeras; interspecies organogenesis; macrophage; pancreas reconstruction; phagoptosis; phosphatidylserine-regulating flippase; xenogeneic barrier

DOI:  https://doi.org/10.1016/j.cell.2026.05.016
Nature. 2026 Jun 03.

LASER couples damage sensing to ESCRT assembly for lysosome repair.

Claire S Goul, Aakriti Jain, Samira Yitiz, Zahra E Soltani, Serim Yang, Simon Rapp, Martina Spacci, Scot Federman, James Sacco, Huinan Li, Lauren D Enriquez, Nalan Liv, Laralynne Przybyla, Roberto Zoncu.

Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.

DOI: https://doi.org/10.1038/s41586-026-10604-6
Cell. 2026 Jun 04. pii: S0092-8674(26)00569-6. [Epub ahead of print]

Deep learning of functional perturbations from condensate morphology.

Anita Donlic, Troy J Comi, Sofia A Quinodoz, Nima Jaberi-Lashkari, Krist Antunes Fernandes, Lifei Jiang, Lennard W Wiesner, Ai Ing Lim, Clifford P Brangwynne.

  Biomolecular condensates compartmentalize the interior of cells to organize complex functions, yet linking molecular interactions within condensates to their mesoscale organization remains a major challenge. To bridge this gap, we developed a neural-network-based framework-Deep-Phase (deep learning of phase-separated condensates)-that uses microscopy images to directly measure condensate morphology changes resulting from pharmacological alterations in associated biochemical processes. We use Deep-Phase to precisely quantify time- and concentration-dependent structural perturbations to the multiphase nucleolus and show that they are tightly coupled to potencies of drugs inhibiting ribosomal RNA (rRNA) transcription and processing. Applying Deep-Phase in a chemical screen, we identify a unique nucleolar morphology and discover a role for a DNA topoisomerase in rRNA processing. Mechanistic studies of this morphology provide insights into how the interfaces between nucleolar sub-compartments are maintained. We demonstrate Deep-Phase's adaptability to diverse cell lines, labeling techniques, and condensates, offering a powerful platform for connecting molecular pathways to cellular mesoscale organization.

Keywords:  RNA biochemistry; RSV; TOP1; biomolecular condensate; deep learning; high-content imaging; morphological profiling; nuclear speckle; nucleolus

DOI:  https://doi.org/10.1016/j.cell.2026.05.010
bioRxiv. 2026 May 20. pii: 2026.01.26.700345. [Epub ahead of print]

Hyaluronan Underlies the Emergence of Form, Fate, and Function in Human Cardioids.

Stefan M Jahnel, Anna Dimitriadi, Julia Kodnar, Vasileios Gerakopoulos, Yajushi Khurana, Maximilian Mayrhauser, Tobias Ilmer, Mohamed Amin Aguech, Adam R Hall, Keisuke Ishihara, Sasha Mendjan.

The extracellular matrix (ECM) is crucial for organ development and disease. Yet, the interplay among cells, function, and the ECM during human cardiogenesis remains obscure. Using human cardioids, we discovered that cardiac mesoderm-synthesized hyaluronan (HA) underlies early cardiac functional development. HA drives cardioid cavity formation through hydrogel swelling and bioscaffolding, critical functions of the cardiac jelly in the early vertebrate heart. During an early developmental window, HA is essential for establishing cardiac cell identity, while at later stages, HA-generated forces promote beating function through mechanosensitive channels. Chamber-specific differences in mechanical sensitivity ensure robust contractions in multi-chambered tissues. Our findings reveal how a single endogenous ECM component orchestrates the co-emergence of form, fate, and function during human organogenesis, opening new avenues for bioengineering physiologically relevant organ models.

DOI: https://doi.org/10.64898/2026.01.26.700345
EMBO J. 2026 Jun 04.

Somatic cells compartmentalise their carbohydrate metabolism to sustain germ cell survival.

Diego Sainz de la Maza, Holly Jefferson, Celine I Brucker, Sonia Paoli, Marc Amoyel.

To ensure success in reproduction, organisms dedicate substantial resources to supporting the germline. In testes, somatic gonadal cells form a barrier that isolates germ cells from circulating nutrients, raising the question of how germ cell metabolism is sustained and how somatic cells ensure that sufficient resources are directed to the germline. Here, we use lineage-specific genetic manipulations and metabolite reporters to show that Drosophila somatic gonadal cells break down circulating sugars to produce and shuttle lactate to germ cells in vivo, thus sustaining their survival. Further, we uncover that somatic cells ensure the allocation of carbohydrate metabolites specifically to germ cell support and that increasing autonomous consumption of carbohydrates in somatic cells increases germ cell death. Thus, germ cell survival depends on functional metabolic compartmentalisation within gonadal somatic support cells.

DOI: https://doi.org/10.1038/s44318-026-00815-y
Nat Commun. 2026 Jun 03.

Asymmetric attrition and secondary chromosome destabilization after double-strand breaks in human embryonic development.

Jenna Turocy, Stepan Jerabek, Woonyung Hur, Jimin Kim, Shuangyi Xu, Qiaojin Zhao, Jia Xu, Alex Robles, Xiangyi Liu, Nathan Treff, Diego Marin, Anna-Katerina Hadjantonakis, Dieter Egli.

DNA repair in human embryos is poorly understood, and double-strand breaks (DSBs) can cause chromosome loss. We show that chromosomal alterations relative to an induced DSB are asymmetric: acentric arms show complementary gains and losses, while centric arms are biased toward losses. Centromeric to the cut site secondary breakage and attrition is extensive. In contrast, break sites at acentric arms are conserved with no secondary breakage. These differences reflect differential forces at the mitotic spindle. Telomeric arms detach from the pro-metaphase spindle while centric truncated chromosomes lag during anaphase, suggesting that the DSB impedes sister chromatid separation. Secondary breakage near the centromere concordant with extensive attrition at the DSB site indicates a DSB can destabilize a chromosome without end-joining of sister chromatids. These results highlight the risks of chromosomal-scale changes in CRISPR-Cas9 genome editing and show that a single DSB can destabilize a human embryo chromosome independent of fusion-breakage cycles.

DOI: https://doi.org/10.1038/s41467-026-73891-7
bioRxiv. 2026 May 28. pii: 2026.05.25.727720. [Epub ahead of print]

Chromatin architecture sets origin licensing capacity.

Eric J Foss, Ilana M Nodelman, Alexa Usenko, Holden Furutani, Ayush Goel, Brandon Lofts, Shawna Miles, Zhiguo Zhang, Gregory D Bowman, Toshio Tsukiyama, Antonio Bedalov.

Replication origin licensing enables complete and faithful genome duplication, yet how chromatin regulates this process in vivo remains unclear. Using MCM-ChEC-seq to track helicase loading from metaphase through G1 in budding yeast, we find that licensing occurs in a rapid, synchronous burst at mitotic exit and then reaches an early plateau despite continued permissive cell-cycle conditions and persistent ORC binding at origins. Here we show that this plateau is imposed by chromatin architecture at replication origins, which limits the extent of origin licensing. Histone H3K56 acetylation marks newly replicated chromatin and is removed at S-phase exit by the deacetylases Hst3 and Hst4. Persistent H3K56ac severely impairs MCM loading without affecting ORC occupancy, indicating that chromatin limits licensing at the helicase-loading step. Strikingly, deletion or catalytic inactivation of the chromatin remodeler Isw2 increases licensing by approximately 40% in wild-type cells and fully suppresses the licensing defect in hst3 Δ hst4 Δ mutants, identifying Isw2 as a physiological inhibitor of origin licensing. Isw2-dependent nucleosome repositioning narrows the origin nucleosome-depleted region and restricts helicase loading. Together, these findings show that chromatin architecture at replication origins sets licensing capacity. Newly replicated chromatin transiently adopts an Isw2-dependent inhibitory configuration that is relieved, but not completely eliminated, by post-replicative chromatin maturation. Genome-wide licensing thus reflects integration of chromatin-imposed licensing capacity with cell cycle-dependent control of licensing timing.

DOI: https://doi.org/10.64898/2026.05.25.727720
bioRxiv. 2026 May 20. pii: 2026.05.19.726235. [Epub ahead of print]

Nucleolar Dynamics During Oogenesis.

Ruoyu Li, Grace McKown, Dai Tsuchiya, Mark Mattingly, Anna Galligos, Michay Diez, Jui Feng Lu, Mary C McKinney, Sean McKinney, Boris Rubinstein, Timothy J Corbin, Melainia McClain, Carrie Carmichael, Victoria A Hassebroek, Stephanie H Nowotarski, Jennifer L Gerton, Kamena K Kostova.

Ribosome biogenesis is a conserved and highly regulated process that starts in the nucleolus, a membrane-less multi-phase organelle. Although the architecture of the nucleolus is known to change due to perturbations, how nucleolar organization is modulated during physiological processes to meet changing translational demands remains unclear. Here, we use zebrafish oogenesis as a developmental context requiring a rapid expansion of translational capacity to investigate the regulation of nucleolar architecture. We show nucleoli undergo coordinated changes in number, size, subnuclear localization, and layering throughout oogenesis. We further demonstrate that nucleoli form around extrachromosomal DNA circles that contain the rDNA locus. Notably, mouse oocytes undergo similar developmental changes in nucleolar layering and phase organization, indicating that remodeling of nucleolar condensates is a conserved feature of oogenesis. These findings reveal previously unexplored regulation of nucleolar architecture as developmental adaptations to changing biosynthetic needs.

DOI: https://doi.org/10.64898/2026.05.19.726235
Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00537-1. [Epub ahead of print] 117459

Kinase condensates enrich ATP and trigger autophosphorylation.

Nicholas E Lea, Lindsay B Case.

  Kinase-mediated signal transduction regulates most cellular processes, and concentration-dependent autophosphorylation is a common mechanism to promote kinase signaling. Many kinases undergo phase separation to form condensates. Despite the central role of autophosphorylation in regulating kinase activity, how condensates impact kinase autophosphorylation has not been systematically studied. Using biochemical reconstitution and cellular studies, we find that phase separation can concentrate kinases to effectively trigger the trans-autophosphorylation of the tyrosine kinases FAK and Abl, as well as the serine/threonine kinase Mst2. Moreover, kinase condensates can create a chemical environment that enriches ATP, and positively charged intrinsically disordered regions are one feature that enrich ATP into condensates. Thus, kinase phase separation is a general mechanism to activate kinase signaling pathways by locally concentrating both kinases and ATP to trigger autophosphorylation.

Keywords:  ABL; CP: Cell biology; CP: Molecular biology; FAK; MST; autophosphorylation; condensates; kinase; phase separation; signaling

DOI:  https://doi.org/10.1016/j.celrep.2026.117459
Curr Biol. 2026 Jun 01. pii: S0960-9822(26)00581-6. [Epub ahead of print]

Importin-β1 functions as a chromatin sensor to position the contractile ring for cytokinesis.

Cecilia Rachelle Brancheriau, Kevin Larocque, Gabrielle Schick, Ioanna Tountas, Alexandra Perlman, Alisa Piekny.

  Cytokinesis, the final step of cell division, relies on ingression of a precisely positioned actomyosin ring. Chromatin-associated Ran-GTP fine-tunes ring position, although the mechanism remains unclear. We hypothesize that depletion of Ran-GTP between segregating chromosomes leads to equatorial enrichment of importins, promoting recruitment of the scaffold protein anillin. However, the role of importins during anaphase is not known. Here, we tested whether importins form a gradient in response to chromatin-associated Ran-GTP and regulate ring assembly in two cultured human cell lines. We endogenously tagged importin-β1 with mNeonGreen in hypotriploid HeLa cells and euploid HCT 116 cells. Live-cell imaging revealed that importin-β1 becomes transiently enriched between segregating chromosomes in anaphase HeLa cells, but not in HCT 116 cells. Using a newly developed optogenetic tool to rapidly disrupt importin-β1 function, we found that importin-β1 is required for ring ingression in HeLa cells. We speculated that the stronger requirement for importin-β1 in HeLa cells reflects differences in chromatin-to-cytosol ratio compared with HCT 116 cells, which could determine whether the Ran-GTP gradient reaches the cortex. Consistently, FLIM-FRET imaging showed that equatorially enriched importin-β1 is Ran-free in HeLa cells, but not in HCT 116 cells. A predictive model of the Ran-free importin-β1 gradient identified factors that modulate gradient formation, including chromatin-to-cytosol ratio. Experimentally decreasing or increasing the chromatin-to-cytosol ratio in HeLa and HCT 116 cells, respectively, altered importin-β1 and anillin localization to resemble the other cell type. Our findings suggest that highly aneuploid cancer cells may depend on importin-mediated anillin recruitment, representing a targetable weakness. VIDEO ABSTRACT.

Keywords:  Ran-gradient; aneuploidy; anillin; chromatin; cytokinesis; importin-β1; mitosis; modeling

DOI:  https://doi.org/10.1016/j.cub.2026.05.005
bioRxiv. 2026 May 19. pii: 2026.05.17.725791. [Epub ahead of print]

Nascent protein retention at polysomes reduces kinetic barriers to self-assembly.

Shriram Venkatesan, Alex Von Schulze, Jeffrey J Lange, Jacob Jensen, Lexie E Berkowicz, Dai Tsuchiya, Ning Zhang, Jennifer Gardner, Scott McCroskey, Ying Zhang, Selene Swanson, Yan Hao, Malcolm Cook, Tong Shu, Liam J Holt, Laurence Florens, Jay R Unruh, Randal Halfmann.

Living proteomes are necessarily far from equilibrium. It is paradoxical, then, that reducing the translation of new proteins -- which should promote equilibration -- instead prolongs life. We investigated the impact of translational flux to nucleation barriers that preserve the solubility of proteins destined to form amyloids or other assemblies. By manipulating translation initiation rates directly or indirectly, across yeast and human cells, and across a variety of supersaturable proteins, we find that accelerating translation initiation broadly accelerates nucleation irrespective of their global concentrations. We showed that this effect was confined to polysomes and was enhanced by N-terminal placement or other features that retained the nascent aggregating domain at polysomes. Finally, we show that intrinsically disordered regions with high tendencies to self-associate are specifically positioned to do so co-translationally, providing evidence that cotranslational nucleation has shaped proteome evolution.

DOI: https://doi.org/10.64898/2026.05.17.725791
Cell. 2026 Jun 04. pii: S0092-8674(26)00573-8. [Epub ahead of print]

Single-cell mapping of regulatory DNA-protein interactions.

Wei-Yu Chi, Sang-Ho Yoon, Evrim Goksel, Levan Mekerishvili, Joe Pelt, Yiyun Lin, Tamara Prieto, John Zinno, Saravanan Ganesan, Catherine Potenski, Franco Izzo, Dan A Landau, Ivan Raimondi.

  Gene expression is controlled by transcription factors (TFs), whose genome binding is shaped by chromatin accessibility and histone modifications, yet mapping these interactions, particularly those with weak affinity or a transient nature, in single cells remains technically challenging. To address this gap, we developed docking and deamination followed by sequencing (D&D-seq), a single-cell immuno-tethering technology for profiling DNA-protein interactions. D&D-seq couples an antibody-binding nanobody to a cytosine base editor, a combination that enables detection of weak or transient factor binding through targeted cytosine-to-uracil editing at protein-bound genomic sites. This approach is compatible with standard single-cell multi-omic workflows and therefore allows integrated analyses of gene regulation. Using assay for transposase-accessible chromatin using sequencing (ATAC-seq) and single-cell ATAC-seq (scATAC-seq), we assessed chromatin accessibility as a functional readout of TF activity, and by coupling D&D-seq with whole-genome sequencing, we captured CTCF binding in both active and inactive chromatin compartments.

Keywords:  clonal hematopoiesis; epigenomics; gene regulation; single-cell; transcription factors

DOI:  https://doi.org/10.1016/j.cell.2026.05.014
J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):

A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.

Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.

Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.

DOI: https://doi.org/10.1083/jcb.202511088
Sci Adv. 2026 Jun 05. 12(23): eaed7115

Lipid composition and mechanical force underlie multi-modal regulation of Piezo1 gating.

George Vaisey, Roderick MacKinnon.

Piezo1 ion channels are widely expressed cellular mechanosensors. They adopt an intrinsically curved shape when closed and are thought to open when mechanical forces applied to the membrane favor a more flattened conformation. In previous studies, Piezo1 channels in lipid vesicles adopted a somewhat flattened conformation mediated by membrane curvature; however, the ion conduction pore remained closed. In line with the closed pore, Piezo1 channels do not open and conduct ions in the kind of lipids that were used in the structural studies. Here, we show first that Piezo1 channels in cell-derived membranes retain the ability to open and conduct ions under mechanical force, and second, that in cell-derived membrane vesicles, they adopt a more completely flattened disk shape associated with large conformational changes within and around the ion conduction pathway. These conformational changes occurring in cell-derived lipid membranes suggest that mechanical force is necessary but insufficient, and that a specific membrane-derived cofactor complements mechanical force to activate Piezo1.

DOI: https://doi.org/10.1126/sciadv.aed7115
Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00042-6. [Epub ahead of print]169 169-191

Mechanisms of germ-soma communication during follicular growth.

Claude Robert, Ricardo Perecin Nociti.

  Communication between cells is essential for orchestrating tissue, organ, and whole-body cohesion. The communication can occur within the same cell (autocrine signaling), between neighboring cells (paracrine signaling), from distant cells (endocrine signaling), and between adjacent cells (juxtacrine signaling). Extracellular vesicle secretions, where messaging molecules like proteins, RNAs, and lipids are embedded in a membrane-enclosed particle released by the signaling cell, allow signaling to occur upon uptake and release of the cargo. Intercellular communications in synchrony between folliculogenesis and oogenesis involve both long-distance and short-distance messaging within the ovarian follicle, which is segmented into different cell types, with the oocyte lying at the center. Cells can generate extensions to increase the range of messaging by reaching out to more distant cells the so-called protrusion-based intercellular communication exemplified by tunneling nanotubes (TNTs), MT-nanotubes (MTNTs), microvilli, filopodia, and cytonemes. In mammalian oocytes, the filopodia from follicular cells that grow towards the oocyte is known as transzonal projections (TZPs). They accumulate large cargos, such as EVs, proteins and RNAs, at the tip creating the gametic synapses. These projections keep the oocyte and follicular cells connected and exchanging cytoplasmic content despite the apparent physical separation caused by the oocyte's zona pellucida. The protective and nurturing nature of follicular cells towards the oocyte, due to the presence of cellular interconnectivity within follicular cells and the oocyte, is conserved between species and is essential for communication, playing a crucial role in the development of a high-quality oocyte.

Keywords:  Filopodia; Intercellular communications; Oocyte; Ovarian follicle; Tran szonal projections

DOI:  https://doi.org/10.1016/bs.ctdb.2026.04.009
Nat Commun. 2026 Jun 03.

Epiblast lumenogenesis is not a mammalian-specific trait.

Antonia Weberling, Natalia A Shylo, Hannah Wilson, Melainia McClain, Richard Kupronis, Alex Muensch, Suzannah A Williams, Florian Hollfelder, Paul A Trainor.

Epiblast lumenogenesis is a hallmark of mammalian embryogenesis, and crucial for the subsequent processes of anterior-posterior patterning and gastrulation. Based on avian model-organisms, reptile epiblasts are thought to form a monolayered flat disc to undergo these developmental events. Here, we report that the squamate, veiled chameleon (Chameleo calyptratus), exhibits epiblast lumenogenesis prior to anterior-posterior patterning. Using SEM, immunofluorescence, and histology techniques, we demonstrate that chameleon epiblast lumenogenesis occurs via a purse-string-like mechanism involving the formation and constriction of concentric rings of supracellular actin cables around the epiblast. Through expression analyses of Nodal1, Nodal2, Cerberus, Lefty, Brachyury, Wnt3A, and Bmp2, and immunostaining for Brachyury, we uncovered a Wnt3A- and Brachyury-positive ring at the edge of the epiblast concomitant with lumenogenesis. Furthermore, our data suggest that anterior-posterior patterning in veiled chameleons may occur independently of Cerberus and Lefty. These processes result in chameleon embryos exhibiting human embryo-like morphology, despite 300 million years of evolutionary separation. Collectively, we show that pre-gastrulation epiblast lumenogenesis is not mammalian-specific but has also evolved in some non-avian reptiles.

DOI: https://doi.org/10.1038/s41467-026-73768-9
bioRxiv. 2026 May 21. pii: 2026.05.19.725802. [Epub ahead of print]

JCAD couples tight junction condensates to actin and RhoA to maintain the endothelial barrier.

Kyle A Jacobs, Yoon-Gu Jang, Fang-Shiuan Leung, Lakyn N Mayo, Torsten Wittmann, Jeffrey O Bush, Matthew L Kutys.

How endothelial cell-cell junctions integrate cytoskeletal, adhesive, and local signaling networks to maintain vascular barrier integrity remains incompletely defined. Here, we identify junctional cadherin 5-associated protein (JCAD) as a modular scaffold that organizes endothelial tight junction architecture by coupling junctional condensates to actin and RhoA signaling. Genetic deletion of Jcad in mice does not affect baseline vascular permeability but causes inflammation-dependent barrier hyperpermeability. JCAD depletion in primary human endothelial cells disrupts tight junction continuity and increases paracellular permeability. Mechanistically, JCAD localizes to ZO-1-positive tight junctions independently of VE-cadherin, directly binds filamentous actin, and forms dynamic actin-associated condensates at cell-cell contacts. Structure-function analysis reveals separable domains mediating tight junction targeting and actin binding, establishing a bipartite architecture that distinctly coordinates junctional signaling and cytoskeletal coupling. Together, these findings identify JCAD as a cell-cell adhesion scaffold that integrates the phase-separated tight junction plaque with actin and RhoA-dependent mechanics, enabling endothelial barrier adaptation to inflammatory stress.

DOI: https://doi.org/10.64898/2026.05.19.725802
Nat Mater. 2026 Jun 01.

Fibronectin matrix remodelling modulates the active nematic dynamics of cancer-associated fibroblasts.

Cécile Jacques, Louisiane Perrin, Joseph Ackermann, Samuel Bell, Olivier Zajac, Ambre Lapierre, Lucas Anger, Clément Hallopeau, Carlos Pérez-González, Lakshmi Balasubramaniam, Xavier Trepat, Benoît Ladoux, Ananyo Maitra, Raphael Voituriez, Danijela Matic Vignjevic.

Cancer-associated fibroblasts are major architects of the tumour stroma, where their aligned, elongated morphology forms a capsule that mechanically restrains tumour expansion. However, it is unclear how this supracellular organization emerges and persists. Here we show that fibroblasts generate a fibronectin matrix that progressively acquires the same nematic order as the cell layer, and that this matrix in turn feeds back to immobilize both cells and topological defects. Using long-term live imaging, traction force microscopy, matrix microfabrication and hydrodynamic modelling, we find that this reciprocal coupling induces an ageing process in which cellular flows and defect motion slow dramatically and ultimately freeze. Despite this arrest, the monolayer remains active, with defects concentrating contractile forces that may represent mechanical weak points. Disrupting fibronectin production fluidizes the capsule, reactivates defect dynamics and compromises its barrier-like function. These findings reveal a self-organizing mechanism by which fibroblasts and their matrix co-evolve to create a mechanically stable, yet active, stromal architecture with direct implications for tumour dissemination.

DOI: https://doi.org/10.1038/s41563-026-02615-5
bioRxiv. 2026 May 22. pii: 2026.05.21.726689. [Epub ahead of print]

Adaptive Replication Fork Acceleration by CDK1-Cyclin B1 Sustains Genome Duplication despite Impaired Origin Firing.

Md Shahadat Hossain, Courtney G Sansam, Krishanu Dhar, Christopher L Sansam.

Although MTBP is essential for replication origin firing, we show here that strong depletion of MTBP can have minor effects on DNA replication rates. This suggests an adaptive process in the DNA replication program, so we examined mechanisms underlying this plasticity. Using an auxin-inducible degron to deplete MTBP, we found that acute suppression of MTBP blocked DNA replication, but that replication rates recovered over time. The timing of this recovery paralleled S phase expression of Cyclin B1, and inhibition of CDK1-Cyclin B1 prevented the recovery. Recovery did not involve restoration of origin firing; instead, replication recovered through accelerated fork progression. Consistent with CDK1 driving this acceleration, ATR inhibition, which activates CDK1, stimulated DNA replication in MTBP-depleted cells through CDK1-dependent increased fork progression rather than increased origin firing. Knockdown of RIF1, a known CDK1 target, phenocopied this effect. Although RIF1 is best known for opposing DDK-dependent MCM phosphorylation at origins, we find that RIF1 knockdown stimulates replication even when DDK is inhibited. Furthermore, RIF1 loss increased replication by accelerating fork progression rather than increasing origin firing. Together, these findings reveal a CDK1-RIF1-dependent mechanism that promotes fork speed during S phase and defines a form of replication plasticity in which fork rate compensates for reduced origin firing.
SIGNIFICANCE STATEMENT: Accurate genome duplication requires thousands of replication origins to fire and replication forks to complete DNA synthesis on schedule. When origin firing is compromised, it is unclear how cells avoid replication failure. We show that cells adapt to persistent loss of the origin-firing factor MTBP by accelerating replication fork progression through a CDK1-RIF1-dependent mechanism, partially compensating for reduced initiation. This adaptive response defines a form of replication plasticity in which cells rebalance origin usage and fork speed to sustain DNA synthesis. This mechanism may be especially relevant in cancer cells or other contexts where replication initiation is chronically stressed.

DOI: https://doi.org/10.64898/2026.05.21.726689
bioRxiv. 2026 May 20. pii: 2026.05.18.726044. [Epub ahead of print]

Direct Mapping of CDK2 Substrates in Embryonic Stem Cells Uncovers an AP-Site Repair Mechanism via HMCES Phosphorylation.

Benjamin R Topacio, Eli-Eelika Esvald, Jürgen Tuvikene, Lida Langroudi, Tapan K Maity, Lisa M Jenkins, Travis H Stracker, Mardo Kõivomägi, S Ali Shariati.

Embryonic stem cells (ESCs) proliferate rapidly while robustly maintaining genomic integrity and exhibiting high cell-cycle kinase activity. How this activity contributes to genome integrity remains unclear. Here, using mouse ESCs engineered to express an analog-sensitive CDK2, we combine thiophosphate labeling with mass spectrometry to define a high-confidence CDK2 substrate landscape. We uncovered 65 CDK2 substrates in total, including both known and previously unrecognized substrates. Among these, HMCES, a sensor of apurinic/apyrimidinic (AP) sites, was identified as a specific cyclin E-CDK2 substrate. We mapped three CDK2-dependent phosphorylation sites in HMCES and showed that phosphorylation of these sites decreased HMCES binding to ssDNA. Mutational analysis further revealed that HMCES docks to cyclin E-CDK2 complexes via the hydrophobic patch on cyclin E. Finally, we demonstrated that HMCES phosphorylation contributes to AP-site repair and promotes ESC proliferation. Together, our findings uncover a CDK2-HMCES signaling axis that links rapid cell-cycle progression to the preservation of genome stability in mouse ESCs.

DOI: https://doi.org/10.64898/2026.05.18.726044
Nat Commun. 2026 Jun 04.

GPI‑anchored protein nanoclusters license migrasome expansion and serve as exocytic platforms for migrasome.

Xiaopeng Li, Ying Li, Renxiang Xie, Haifeng Jiao, Li Yu.

Migrasomes are dynamic organelles that form on migrating cells and mediate intercellular communication through secretory cargo release. Expansion of migrasomes has classically been attributed to tetraspanin-enriched microdomains (TEMs). Here we show that nanoclusters of glycosylphosphatidylinositol-anchored proteins (GPI-APs) act upstream to license expansion, while TEMs provide the stabilizing scaffold. We find that GPI-AP biosynthesis is important for migrasome formation, and that insertion of the GPI anchor alone is sufficient to drive precursor expansion, producing unstable migrasomes that retract. Stimulated emission depletion (STED) microscopy resolves a meshwork of GPI-AP nanoclusters interlocked with, yet largely segregated from, tetraspanin domains in stable migrasomes. Exocytic machinery localizes to GPI-AP regions, where secretion occurs. In cells that naturally generate unstable migrasomes, elevated tetraspanin levels convert them into stable vesicles. We propose a two-module architecture generating unstable, secretion-specialized migrasomes in some cells and stable migrasomes as extracellular extensions of the secretory pathway in others.

DOI: https://doi.org/10.1038/s41467-026-73674-0
bioRxiv. 2026 May 25. pii: 2026.05.24.727551. [Epub ahead of print]

Rapid actin filament turnover maintains cortical connectivity while allowing for cell cortex deformation and flow.

Rachel S Kadzik, Ondrej Maxian, Isaiah Thomas, David R Kovar, Edwin M Munro.

Cells harness the actomyosin contractility of the cell cortex to drive rapid cellular deformations and intracellular flows during cell polarization, migration, and division. To sustain contractile network architectures while allowing for network deformation and remodeling, the balance of actin filament assembly and disassembly must be finely tuned, but how this is coordinated in the cell remains obscure. Here, we combine quantitative measurements and manipulations of filament assembly and disassembly rates with live imaging of network contractility dynamics in the C. elegans zygote to identify co-dependencies between assembly rates, disassembly rates, and large-scale deformations of the cortical actin network. We find that strong reductions in either filament assembly or disassembly rates both result in actin cortex collapse, but each perturbation has distinct effects on actin cortex and cell membrane dynamics. These findings demonstrate that rapid turnover, involving tightly coordinated assembly and disassembly, allows the cortex to maintain a connected architecture while undergoing rapid deformation and coherent flow.

DOI: https://doi.org/10.64898/2026.05.24.727551
Cell Rep. 2026 Jun 04. pii: S2211-1247(26)00581-4. [Epub ahead of print]45(6): 117503

A progenitor cell population contributes to prenatal injury repair and neonatal antimicrobial defense in the small intestine.

Yonghui Shen, Chunlin Li, Hanqiong Zhang, Huidong Liu, Lianzheng Zhao, Ye-Guang Chen.

  The specialized types and functions of epithelial cells in the adult small intestine have been well elucidated, but remain poorly understood in the embryonic small intestine. Through integrating single-cell RNA sequencing with functional studies using mouse and organoid models, we identify small intestinal sentinel progenitor cells (SISPCs), marked by Lysozyme1 (Lyz1), in the embryonic and neonatal mouse small intestine. Distinct from Lyz1+ Paneth cells, SISPCs exhibit dynamic spatiotemporal patterning and stemness features during intestinal development. Notably, embryonic SISPCs display strong stemness potential in the proximal small intestine, whereas embryonic Lgr5+ cells exhibit greater stem potency in the distal region. In addition, SISPCs play a crucial role in the prenatal intestinal injury repair via the DUSP-p38 signaling axis and contribute to the neonatal antimicrobial defense. Our findings reveal SISPCs play a pivotal role in gut homeostasis and defense during development, and suggest them as potential therapeutic targets for developmental gut disorders.

Keywords:  CP: developmental biology; CP: immunology; SISPCs; antimicrobial defense; embryonic small intestine; injury repair; stemness

DOI:  https://doi.org/10.1016/j.celrep.2026.117503
bioRxiv. 2026 May 26. pii: 2026.05.25.727721. [Epub ahead of print]

Embryo-scale Visual Cell Sorting reveals a conserved transcriptomic signature of nucleolar size linked to proteostasis.

Hyeon-Jin Kim, Sriram Pendyala, Josephine Lin, Tony Cooke, Gang Li, William Stafford Noble, Xinxian Deng, Christine M Disteche, Cole Trapnell, Douglas M Fowler.

Nucleoli, nuclear speckles and other compartments regulate transcription, RNA processing, and chromatin organization within the nucleus, yet the relationship of their morphology to developmental gene expression programs in vivo is poorly understood. Here, we develop a high-throughput Visual Cell Sorting (VCS) workflow for fixed cells and nuclei that combines antibody-based photoconversion; GPU-accelerated, real-time image analysis; and three-level single-cell combinatorial indexing RNA-seq (sci-RNA-seq3) to link nuclear compartment morphology to single-nucleus transcriptomes at embryo scale. We use VCS to analyze and sort over 1 million mouse embryo-derived nuclei by nucleolar, nuclear speckle, or nuclear size and construct a transcriptional atlas annotated with nuclear compartment phenotypes. Nuclear compartment size varies both between and within lineages and is shaped by proliferation and differentiation. In extracellular matrix protein-producing cell types such as fibroblasts, chondrocytes, and osteoblasts, nucleolar enlargement is uncoupled from cell cycle, and in erythroid cells exhibit a sharp nucleolar contraction preceding cell-cycle exit. We identify a 41-gene transcriptional signature whose expression tracks nucleolar size, enriched for ribosome biogenesis, mitochondrial metabolism, unfolded protein response, stress granule, and ubiquitin-proteasome pathway components. We used this nucleolar transcriptional signature to annotate mouse, zebrafish and human developmental atlases with nucleolar size information, revealing a conserved coupling between nucleolar activity and proteostasis programs. Our work establishes Visual Cell Sorting as a scalable platform for mapping image-based phenotypes to molecular programs; details the relationship between nuclear compartment phenotypes and development; and provides a transcriptional signature to estimate nucleolar size from existing single-cell datasets.

DOI: https://doi.org/10.64898/2026.05.25.727721
bioRxiv. 2026 May 22. pii: 2026.05.21.726120. [Epub ahead of print]

Simultaneous brain-wide single-cell recording resolves spatiotemporal memory architecture.

Dongqing Shi, Yongjie Hou, Yixiao Yan, Tian-Hao Zhang, William C Joesten, Peng Liu, Yixuan Wang, Mehul Gautam, Jormay Lim, Lirong Zheng, Jonathan Gould, BumJin Ko, Xiaoman Niu, Mou-Chi Cheng, Jung-Chien Hsieh, Florian Levet, Dawen Cai, Anne Draelos, Denise J Cai, Donglai Wei, Changyang Linghu.

Many fundamental mammalian brain functions emerge from the coordinated activity of cells distributed across large, brain-wide networks. To understand these processes in healthy and diseased states, ideally one would simultaneously measure and analyze single-cell activity at the brain-wide scale, an enduring challenge for live-measurement approaches that often face an inherent tradeoff between spatial resolution and scale. Here, we present GLOBE (sinGle-cell spatiotemporaL recOrding Brain-widE), a technology for brain-wide single-cell recording of cellular activity in vivo with spatiotemporal resolution, physiological sensitivity, and parallelization-accelerated readout. GLOBE leverages genetically encoded intracellular protein tape recorders and a high-throughput computational platform for integrated image and signal analysis. GLOBE records analog signal amplitudes across a continuous time axis, requires only standard light microscopy for in situ readout, and is compatible with expansion microscopy and RNA readouts. We applied GLOBE to simultaneously record transcriptional activity of the immediate early gene Fos in up to 219,703 neurons simultaneously across a single mouse brain over 5.5 continuous days, with a timestamp precision of 3.1-6.7 hours (median absolute error), a local recording density of 69-90% of neurons per imaging field of view, and a post-mortem imaging readout speed of 2.9 seconds per neuron on average. GLOBE resolves the brain-wide spatiotemporal structure of single-cell activity, revealing that Fos transcriptional dynamics associated with fear learning and memory retrieval are distributed across the brain with region-specific temporal heterogeneity, and that the variance of this structure scales down as the number of sampled cells increases. We envision GLOBE to have broad applications for dissecting and decoding physiological and pathological processes at the brain-wide scale.

DOI: https://doi.org/10.64898/2026.05.21.726120
Cell Syst. 2026 Jun 04. pii: S2405-4712(26)00103-1. [Epub ahead of print] 101621

Widespread transcriptional memory shapes heritable states and functional heterogeneity in cancer and stem cells.

Yongjie Lin, Xiangru Chen, Long Wu, Yutong Zhou, Yihan Lin.

  Recent studies show that non-genetic heterogeneity, particularly through heritable cell states, shapes cancer evolution and developmental trajectories. However, single-cell snapshots lack temporal information to identify these states. We employ lineage-resolved single-cell transcriptomics to map heritable cell states that persist across divisions, distinguishing them from transient fluctuations. We reveal that heritable states are underpinned by widespread transcriptional memory, whereby heritable gene expression defines two classes of states: clustered states, characterized by clustered gene expression, and latent states, marked by non-clustered gene expression. This memory shows partial conservation across cell types and conditions and appears to be maintained by robust epigenetic mechanisms that are resistant to environmental perturbations. Functionally, memory genes predict critical behaviors, including metastatic potential and lineage commitment, with latent-state genes often outperforming clustered-state genes. Our findings establish transcriptional memory as a potential basis for heritable cellular heterogeneity, providing a framework for understanding functional cellular variation across biological systems.

Keywords:  CORAL; cancer; cellular heterogeneity; heritable cell state; lineage tracing; memory genes; single-cell transcriptomics; stem cells; transcriptional memory

DOI:  https://doi.org/10.1016/j.cels.2026.101621
Cell. 2026 Jun 02. pii: S0092-8674(26)00567-2. [Epub ahead of print]

Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense.

Chew Chai, Eliya Sultan, Souradeep R Sarkar, Lihan Zhong, Dania Nanes Sarfati, Orly Gershoni-Yahalom, Christine Jacobs-Wagner, Hawa Racine Thiam, Benyamin Rosental, Bo Wang.

  Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells-T cells, natural killer cells, and neutrophils. Here, we identify "ruptoblasts," a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, "ruptosis," triggered by activin, a multifunctional hormone acting as an inflammatory cytokine. Excessive activin-induced through protein injection, genetic chimerism, or bacterial infection-initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating nearby cells, bacteria, and even mammalian cells within minutes. Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions. Mechanistically distinct from known cytotoxic and cell death mechanisms, the explosive nature of ruptosis relies on endoplasmic reticulum (ER)-derived calcium and cytoskeleton-dependent signal amplification. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.

Keywords:  activin signaling; cell death/destruction; cytotoxicity; evolution of immune system; extreme cell biology; genetic chimeras; glandular/secretory cell types; hormonal surveillance; planarian

DOI:  https://doi.org/10.1016/j.cell.2026.05.008
Development. 2026 Jun 04. pii: dev.205402. [Epub ahead of print]

Zebrafish knock-in lines enabling live visualization of extracellular matrix dynamics during development and regeneration.

Jingwen Shen, Ranjay Jayadev, Pierre Gillotay, Jianhong Ou, Ashley Rich, Madison L Zimmerman, Kazunori Ando, Stefano Di Talia, David R Sherwood, Kenneth D Poss.

  Extracellular matrix (ECM) plays fundamental roles in animal development, regeneration, and disease. The difficulty of tagging endogenous matrix proteins in vertebrates has limited the understanding of ECM composition and dynamics in complex tissues. To visualize vertebrate ECM components, we tagged zebrafish Laminin, gamma 1 (Lamc1), Collagen, type I, alpha 2 (Col1a2), and Transforming growth factor, beta-induced (Tgfbi) using C-terminus in-fusion genome editing. Analysis of these knock-in lines revealed distinct expression of each protein in various tissues during development and regeneration. Fluorescence recovery after photobleaching analysis further indicated that Lamc1 is stable in fin fold matrix but more dynamic in myoseptal matrix of developing zebrafish, while Col1a2 and Tgfbi are stable matrix components in myosepta. Strikingly, we found that Col1a2-mScarlet protein accumulates at the amputation plane during tailfin regeneration, where it remains concentrated for several days and distant from the regeneration blastema. This "foundation" region also displays a distinct transcriptome suggesting active and dedicated events at the base of the regenerating appendage. Our resource enables live capture of ECM dynamics that can identify new events in developing and regenerating zebrafish.

Keywords:  Extracellular matrix; Fusion protein knock-in; Protein dynamics; Tissue regeneration; Zebrafish

DOI:  https://doi.org/10.1242/dev.205402
bioRxiv. 2026 May 20. pii: 2026.05.18.726076. [Epub ahead of print]

BMP signaling during gastrulation pre-patterns the dorsal spinal cord.

Hannah Greenfeld, Daniel E Wagner.

The classic model of dorsal spinal cord patterning proposes that roofplate-derived BMP patterns dorsal interneuron subtypes in a concentration-dependent manner. However, genetic perturbations of BMP pathway components produce variable effects, challenging this model. Here we implemented single-cell profiling, fate mapping, and mosaic perturbations to determine when BMP signaling patterns dorsal neural fates in vivo . Contrary to the classic model, we demonstrate that dorsal fates are patterned by BMP signaling during gastrulation. Following neural tube formation, BMP signaling continues but plays limited roles in domain specification and maturation. Fate mapping revealed that dorsal progenitors originate from the ventral gastrula, adopting BMP-dependent transcriptional states that prime dorsal neural fate. We propose that dorsal neural fates are initially patterned by gastrulation-stage sources of BMP, prior to roofplate induction.

DOI: https://doi.org/10.64898/2026.05.18.726076
Nat Cell Biol. 2026 Jun 01.

Segmental specification of the human female fetal reproductive tract revealed by spatiotemporal dynamics.

Zuoxi He, Qian Wang, Lisha Ding, Yisi Wang, Hongcheng He, Wuyue Han, Siyao Li, Jing Fu, Can Luo, Jingyu Li, Rui Gao, Yueyue Chen, Ling Mei, Dongmei Wei, Jian Meng, Yueting Zhang, Tao Wang, Xiaoyu Niu.

The proper development of the human female reproductive tract (FRT) is essential for reproductive competence. However, the mechanisms underlying its segmental specialization remain underexplored. This gap limits our knowledge of congenital anomalies and adult reproductive disorders. Herein, we build a spatiotemporal transcriptomic atlas of the distinct human FRT segments development from gestational week (GW) 10 to 25, capturing cellular composition and lineage dynamics. We discovered that the upper and lower segments of FRT are composed of distinct mesenchymal and epithelial cell subpopulations starting from as early as GW10. Mesenchymal lineages in different segments arise from distinct mesenchymal stem cell (MSC)-like cells and undergo critical differentiation between GW13 and GW22, giving rise to fibroblasts and smooth muscle cells. TGF-β and PDGF signalling pathways seem to play a pivotal role in guiding these distinct fate transitions. Concurrently, epithelial development exhibits region-specific trajectories: upper and lower FRT epithelial cells originate from different stem-like populations and undergo key transitions between GW14 and GW22. Specifically, we identify MSC-like1 and MSC-like2 as regulatory populations that may influence epithelial differentiation via WNT5A-FZD and IGF1-IGF1R signalling pathways in the upper and lower FRT, respectively. This finding highlights a spatially specific mesenchymal-epithelial crosstalk that shapes regional epithelial identity. Altogether, our work provides a comprehensive insight into the segmental specification and coordinated lineage decisions that offer foundational resource for understanding FRT development, congenital anomalies and tissue engineering.

DOI: https://doi.org/10.1038/s41556-026-01962-4
Nat Rev Mol Cell Biol. 2026 Jun 03.

Tight junction structure, assembly and (dys)function.

Dorothee Günzel, Martin Lehmann, Alf Honigmann.

Tight junctions (TJs) regulate paracellular permeability, cell polarity and cell mechanics of barrier-forming tissues. This Review explores how TJs adapt their structure and function across tissues, with a focus on the claudin-based strand network, its regulation by zonula occludens scaffold proteins and its dysfunction in human diseases. We discuss recent insights into TJ assembly through biomolecular condensation, highlighting how scaffold self-organization integrates adhesion, actin dynamics and polarity cues. We examine TJ maintenance across timescales, from rapid protein turnover to long-term remodelling during development. Finally, we focus on TJ function in lumen formation and review TJ dysfunctions and strategies to target TJ proteins therapeutically. We close by highlighting emerging approaches to tackle open structural, mechanical and functional questions of TJ physiology and pathology.

DOI: https://doi.org/10.1038/s41580-026-00978-w
J Cell Biol. 2026 Aug 03. pii: e202409118. [Epub ahead of print]225(8):

Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.

Julius Winter, Juan C Landoni, Keaton B Holt, Sheda Ben Nejma, Emine Berna Durmus, Tatjana Kleele, Elena F Koslover, Suliana Manley.

In functionally polarized cells, mitochondria can form distinct subpopulations, positioned at sites of varying metabolic and energetic demands. Thus far, the potential presence of such subpopulations and implications of their intracellular trafficking in immobile and proliferative cells remain largely undescribed, despite such cells serving as key models. Here, we use substrate micropatterning to create reproducible morphologies of cultured immortalized cells, enabling us to define mitochondrial subpopulations and follow their trafficking by photoactivation. We discovered that mitochondrial material is dispersed asymmetrically throughout the cell via biased anterograde transport from the perinuclear area. Combining quantitative analysis and in silico modeling, we characterize the causes and consequences of unbalanced mitochondrial trafficking. Our findings indicate that this bias is required to distribute new material resulting from perinuclear mitochondrial biosynthesis to sustain mitochondrial mass distribution across the cell and to maintain normal network connectivity.

DOI: https://doi.org/10.1083/jcb.202409118
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2535527123

Subsarcomeric regulation of thin and thick filaments in skeletal muscle myofibrils.

Kristina Sliogeryte, Luca Fusi.

  Muscle contraction relies on the coordinated activation of myosin motors from a folded-OFF state on the thick filament surface and their actin tracks on the thin filaments in response to calcium. Thick filaments contain distinct regulatory zones defined by the presence of myosin-binding protein C (MyBP-C) and titin super-repeats, but the control of myosin OFF/ON states within these zones has not been directly resolved. Here, we do so by fluorescence polarization microscopy (FPM) in myofibrils isolated from rabbit fast skeletal muscle. Using orientation-specific probes on myosin we show that folded-OFF motors are enriched in the MyBP-C-containing C zone in relaxed myofibrils, indicating that MyBP-C stabilizes the myosin OFF state in this filament domain. Under titin-based passive tension or partial calcium activation, active motors are enriched in the D zone at the filament tips, which lacks MyBP-C, suggesting that D-zone motors are activated at lower filament stress. Troponin probes further reveal that myosin enhances thin-filament activation in the region of filament overlap and drives the stress-dependent activation of the thin filament into adjacent nonoverlap regions. These findings uncover zone-specific control of myofilament activation within the sarcomere and establish FPM as a powerful tool for investigating disease-linked myofilament protein variants and therapeutic modulation.

Keywords:  muscle regulation; myosin; sarcomere; skeletal muscle; troponin

DOI:  https://doi.org/10.1073/pnas.2535527123