{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T10:25:59Z","timestamp":1773138359096,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,5]]},"group-title":"Neuroscience","reference-count":42,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01NS112713"],"award-info":[{"award-number":["R01NS112713"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01NS138405"],"award-info":[{"award-number":["R01NS138405"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DOD","award":["TS230053"],"award-info":[{"award-number":["TS230053"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Retinoid-related orphan receptor gamma (ROR\u03b3) is a lineage-defining transcription factor for T helper 17 (Th17) cells and has long been considered selectively expressed within the immune system. However, accumulating evidence has implicated Th17 cells and other ROR\u03b3-expressing immune populations in embryonic brain development and central nervous system (CNS) function. Notably, ROR\u03b3-Cre\u2013mediated deletion of the tuberous sclerosis complex (TSC) has been reported to cause spontaneous seizures and premature lethality, leading to the conclusion that ROR\u03b3-expressing immune cells directly regulate CNS physiology. Using multiple ROR\u03b3-based reporter mouse lines, we identified unexpected and widespread neuronal labeling throughout the forebrain and cerebellum. ROR\u03b3-Cre:GFP\n                  <jats:sup>f\/<\/jats:sup>\n                  mice exhibited robust GFP expression in neurons despite the absence of detectable T cells in the brain. Neuronal recombination was evident prenatally and independently validated using the mT\/mG reporter line, indicating transient ROR\u03b3 expression in embryonic neurons. In contrast, a ROR\u03b3-GFP reporter showed no detectable ROR\u03b3 expression in the postnatal brain, either at baseline or following pilocarpine-induced status epilepticus. These findings demonstrate that ROR\u03b3 expression is not restricted to the immune lineage and reveal previously unrecognized developmental expression in the embryonic brain. Consequently, seizures observed following ROR\u03b3-Cre\u2013mediated deletion of TSC1 are unlikely to arise from ROR\u03b3-expressing immune cell\u2013dependent mechanisms but instead reflect direct neuronal loss of TSC1. Our results call for careful reinterpretation of prior studies attributing CNS phenotypes to ROR\u03b3-expressing immune cells based on ROR\u03b3-Cre\u2013driven genetic models.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>This work identifies transient neuronal ROR\u03b3 expression as a critical confounder in immune-targeted genetic studies and reveals a previously unrecognized embryonic expression of ROR\u03b3 in neurons that may contribute to neurodevelopment. Our findings further raise the possibility that embryonic neurons represent unintended off-targets when deploying therapeutic strategies involving ROR\u03b3 ligands.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.03.709291","type":"posted-content","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T05:25:28Z","timestamp":1772774728000},"source":"Crossref","is-referenced-by-count":0,"title":["Neuronal expression of Retinoid-Related Orphan Receptor Gamma (ROR\u03b3) and revisiting its role in the Central Nervous System"],"prefix":"10.64898","author":[{"given":"Logan","family":"Reid","sequence":"first","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srikar","family":"Ganapathiraju","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Mancinelli","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Kagan","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gia","family":"Sprouse","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Fazio","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"German","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuangxin","family":"Fan","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rojana","family":"Saengsot","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Feustel","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7129-1250","authenticated-orcid":false,"given":"Yunfei","family":"Huang","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY, USA 12208"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026030913051859000_2026.03.03.709291v1.1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3109\/10799893.2012.692120","article-title":"The interplay between retinoic acid receptor-related orphan receptors and human diseases","volume":"32","year":"2012","journal-title":"J Recept Signal Transduct Res"},{"key":"2026030913051859000_2026.03.03.709291v1.2","doi-asserted-by":"crossref","unstructured":"Clark EA , Rutlin M , Capano LS , Aviles S , Saadon JR , Taneja P , et al. 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