{"paper_id":"36d4e324-93ac-4f36-bc72-a2a1bd3b8937","body_text":"Cortical tension as a mechanical barrier to safeguard against premature differentiation during neurogenesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cortical tension as a mechanical barrier to safeguard against premature differentiation during neurogenesis Hongyan Zou, Daniel Halperin, Chrystian Junqueira Alves, Marcelle Rodrigues Lemos, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7725502/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Neuronal differentiation requires coordinated gene reprogramming and morphodynamic remodeling. How mechanical forces integrate with nuclear gene programs during neurogenesis remains unresolved. Here, we identify cortical tension as a mechanical barrier that safeguards against premature neuronal differentiation. Deletion of Plexin-B2, a guidance receptor controlling actomyosin contractility, lowers this barrier, enabling neurite outgrowth and accelerating neuronal lineage commitment. We show that coupling of extrinsic differentiation cues with intrinsic morphodynamics is essential for stabilizing neuronal fate and that cortical barrier and epigenetic barrier act in concert to regulate developmental timing. In cerebral organoids, Plexin-B2 ablation triggered premature cell-cycle exit and differentiation, resulting in progenitor pool depletion and neuroepithelial disorganization, phenotypes echoing intellectual disability in patients with rare pathogenic PLXNB2 variants. Our studies demonstrate that cortical tension functions as mechano-checkpoint that regulates the onset of neurogenesis. Lowering this barrier may provide a strategy to accelerate induced neuron generation and maturation for CNS disease modeling. Biological sciences/Neuroscience/Neurogenesis Biological sciences/Stem cells/Stem-cell differentiation Neuronal differentiation Plexin-B2 Cortical barrier Induced neuron Cerebral organoid Corticogenesis Neurodevelopment Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MovieS1hNPCD6ActinbTubNucSpot.mp4 Supplemental Movie S1 SupplemetaryMaterialsFigsTables.pdf Supplemental Figures S1 - S8 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7725502\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":537612668,\"identity\":\"dbfdfe92-0c9a-47a4-978d-02cead01ec35\",\"order_by\":0,\"name\":\"Hongyan 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