Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes | 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 Biological Sciences - Article Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes Amanda Sierra, Marta Pereira-Iglesias, William Martinson, Carles Falco, and 27 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8344753/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Early immune perturbations increase the risk of brain disorders, yet the mechanisms underlying the functional maturation of microglia, the brain resident immune cells, remain poorly defined. Here, we used mathematical modeling of hippocampus and cerebellum to reconstruct postnatal microglial development. We identified a proliferative-to-quiescent (P/Q) switch around P3/P4 that preceded the acquisition of morphological complexity and efficient phagocytosis and was accompanied by changes in cell-cycle dynamics and metabolic state. This P/Q switch was recapitulated in repopulation contexts in mice and in the fetal human brain. Pharmacological and genetic perturbations of proliferation impaired subsequent morphological complexity and phagocytosis efficiency. Finally, microglial developmental maturation was associated with chromatin remodeling and driven by the epigenetic regulator Ikaros. These findings uncover the milestones of microglial development, revealing a potential period of early vulnerability and establishing an unexpected linkage between proliferation and phagocytosis essential to understanding how these processes are coordinated in neurodegenerative disorders. Biological sciences/Neuroscience/Glial biology Biological sciences/Neuroscience/Development of the nervous system Biological sciences/Neuroscience/Neuroimmunology microglia development proliferation phagocytosis epigenetic modulators Ikaros population modeling Bayesian parameter inference Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTextfinalsubmittedwfigures.pdf Supplementary Text Cite Share Download PDF Status: Under Review 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-8344753","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":574674747,"identity":"c81ae33f-62ae-4d4b-a39d-fb76239ace7d","order_by":0,"name":"Amanda 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