MeCP2 Governs Maternal Hyperandrogenism-Induced Cortical Defects and Autism-like Behaviors via Noncanonical AR-Dependent Regulation of Mef2c

MeCP2 Governs Maternal Hyperandrogenism-Induced Cortical Defects and Autism-like Behaviors via Noncanonical AR-Dependent Regulation of Mef2c | 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 MeCP2 Governs Maternal Hyperandrogenism-Induced Cortical Defects and Autism-like Behaviors via Noncanonical AR-Dependent Regulation of Mef2c Yu-Meng Wang, Yanyan Jia, Yu Wu, Qiaohang Zhao, Yumeng Guo, Li Zhang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6731184/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 Elevated androgen levels during pregnancy have been associated with an increased occurrence of several neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD) and intellectual disability. Nevertheless, the precise mechanisms through which androgens affect brain development remain poorly comprehended. By employing a prenatal hyperandrogenic mouse model, we observed abnormal cerebral cortex development and autism-like behaviors predominantly in male offspring, effects could be prevented by an androgen receptor (AR) blocker. Mechanistically, we identify the transcription factor MEF2C as a critical downstream target of androgen signaling in cortical neurogenesis. Remarkably, AR-mediated transcriptional upregulation of Mef2c occurs independently of canonical androgen response elements (AREs). Instead, AR interacts with MeCP2 and co-occupies the MeCP2 binding site within the Mef2c gene promoter region. Knocking down Mecp2 could also reverse the effects of hyperandrogen on cortical neurogenesis. Moreover, MeCP2 duplication upregulated the MEF2C level and cortical neurogenesis in male offspring without prenatal hyperandrogen exposure, and knocking down Mef2c or blocking AR both could restore the effects of MeCP2 duplication on cortical neurogenesis in male offspring without prenatal hyperandrogen exposure. Collectively, our results elucidated a MeCP2-dependent non-ARE regulation pathway under androgen in cortical development. Biological sciences/Developmental biology/Neurogenesis/Developmental neurogenesis Biological sciences/Neuroscience/Development of the nervous system/Neuronal development cortex development Autism Hyperandrogen Mef2c MeCP2 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryMaterials.pdf Supplemental Information Sourcedata.xlsx Source data 1 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6731184","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":469405546,"identity":"4708cbd8-5266-44cc-b4ab-f46e60fd3641","order_by":0,"name":"Yu-Meng 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Nevertheless, the precise mechanisms through which androgens affect brain development remain poorly comprehended. By employing a prenatal hyperandrogenic mouse model, we observed abnormal cerebral cortex development and autism-like behaviors predominantly in male offspring, effects could be prevented by an androgen receptor (AR) blocker. Mechanistically, we identify the transcription factor MEF2C as a critical downstream target of androgen signaling in cortical neurogenesis. Remarkably, AR-mediated transcriptional upregulation of \u003ci\u003eMef2c\u003c/i\u003e occurs independently of canonical androgen response elements (AREs). Instead, AR interacts with MeCP2 and co-occupies the MeCP2 binding site within the \u003ci\u003eMef2c\u003c/i\u003e gene promoter region. Knocking down \u003ci\u003eMecp2\u003c/i\u003e could also reverse the effects of hyperandrogen on cortical neurogenesis. 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