{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:59:28Z","timestamp":1790312368477,"version":"4.1.0"},"posted":{"date-parts":[[2025,12,24]]},"group-title":"Neuroscience","reference-count":99,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["NS095654"],"award-info":[{"award-number":["NS095654"]}]},{"name":"NIH","award":["MH106934"],"award-info":[{"award-number":["MH106934"]}]},{"name":"NIH","award":["MH116488"],"award-info":[{"award-number":["MH116488"]}]},{"name":"NIH","award":["MH110926"],"award-info":[{"award-number":["MH110926"]}]},{"name":"NIH","award":["MH129981"],"award-info":[{"award-number":["MH129981"]}]},{"name":"NIH","award":["MH129751"],"award-info":[{"award-number":["MH129751"]}]},{"name":"NIH","award":["MH122681"],"award-info":[{"award-number":["MH122681"]}]},{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"crossref","award":["SFARI #736613"],"award-info":[{"award-number":["SFARI #736613"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behavior, and the motor cortex (MC), which executes movement. A hallmark of primate brain evolution is PFC expansion accompanied by a posterior displacement of the MC. Retinoic acid (RA) signaling has emerged as a key regulator of PFC specification and expansion. However, the mechanisms that spatially confine RA signaling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we defined an RA-associated gene regulatory network (RA-GRN) in the developing human PFC and identified\n                  <jats:italic>MEIS2<\/jats:italic>\n                  , which encodes a transcription factor linked to intellectual disability and autism spectrum disorder (ASD), as its key hub of this network. Conditional deletion of\n                  <jats:italic>Meis2<\/jats:italic>\n                  in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories toward motor-like molecular and connectional features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with\n                  <jats:italic>Meis2<\/jats:italic>\n                  loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signaling itself, is markedly reduced in the developing medial prefrontal cortex (mPFC). These findings revealed a conserved autoregulatory loop: RA \u2192 MEIS2 \u2192 ALDH1A3 \u2192 RA that reinforces a PFC-enriched RA gradient and organizes the MC\u2013PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signaling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to psychiatric disorders.\n                <\/jats:p>","DOI":"10.64898\/2025.12.23.696038","type":"posted-content","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T10:45:16Z","timestamp":1766573116000},"source":"Crossref","is-referenced-by-count":2,"title":["A Retinoic Acid Autoregulatory Loop Governing Prefrontal-Motor Arealization"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2277-5440","authenticated-orcid":false,"given":"Lin","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5588-4583","authenticated-orcid":false,"given":"Mikihito","family":"Shibata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0926-8076","authenticated-orcid":false,"given":"Saejeong","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8380-2882","authenticated-orcid":false,"given":"Yuting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3817-1983","authenticated-orcid":false,"given":"Iva","family":"Salamon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0240-9304","authenticated-orcid":false,"given":"Suel-Kee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6761-691X","authenticated-orcid":false,"given":"Akemi","family":"Shibata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2655-8602","authenticated-orcid":false,"given":"Ashley","family":"Deveau-French","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2155-9922","authenticated-orcid":false,"given":"Xoel","family":"Mato Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5139-9758","authenticated-orcid":false,"given":"Suxia","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2218-5590","authenticated-orcid":false,"given":"Timothy","family":"Nottoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4441-9359","authenticated-orcid":false,"given":"Narjes","family":"Rohani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9112-5148","authenticated-orcid":false,"given":"Stephan J.","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-8888","authenticated-orcid":false,"given":"Rothem","family":"Kovner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3924-426X","authenticated-orcid":false,"given":"Kartik","family":"Pattabiraman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-9619","authenticated-orcid":false,"given":"Nenad","family":"Sestan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122905500428000_2025.12.23.696038v2.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.24.1.167"},{"key":"2025122905500428000_2025.12.23.696038v2.2","doi-asserted-by":"crossref","unstructured":"Stuss, D. 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