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Previous studies demonstrated Zinc Finger transcription factor of the Cerebellum 3 (ZIC3) to regulate forebrain development, and\n                    <jats:italic>Zic1\/Zic3<\/jats:italic>\n                    compound mutant mice displayed reduced OB size. However, the precise role of ZIC3 in TH regulation remains elusive. In this study, we attempted to understand the role of ZIC3 in TH regulation and its underlying mechanism. While loss of function of\n                    <jats:italic>Zic3<\/jats:italic>\n                    in OB-derived neurons led to down-regulation of TH expression, it could be rescued by over-expression of shRNA-resistant\n                    <jats:italic>Zic3<\/jats:italic>\n                    . Immunohistochemistry of OB of\n                    <jats:italic>Zic3<\/jats:italic>\n                    null mice showed a similar reduction in expression of TH. Promoter of TH lacks the consensus ZIC3 binding region, and mechanistic insights revealed ZIC3 to regulate TH expression by interacting with ER81, a known TH regulator. ZIC3 interaction with ER81 is indispensable for ER81 binding to the\n                    <jats:italic>Th<\/jats:italic>\n                    promoter, and it fine-tunes ER81-mediated\n                    <jats:italic>Th<\/jats:italic>\n                    regulation in OB. In MB, where TH levels are highest after birth, ZIC3 regulates TH expression both in vitro and in vivo. TH was significantly reduced in P0\n                    <jats:italic>Zic3<\/jats:italic>\n                    null mice, as well as in\n                    <jats:italic>Zic3<\/jats:italic>\n                    shRNA stereotactically delivered in 7-month-old mice. Mechanistically, in the absence of ER81 in MB, ZIC3 chooses an alternative approach of binding to\n                    <jats:italic>Pitx3<\/jats:italic>\n                    promoter\u2014a Dopaminergic (DA) fate determinant. Under the ectopic expression of ER81 in MB derived neurons, the propensity of ZIC3 binding to\n                    <jats:italic>Pitx3<\/jats:italic>\n                    promoter is compromised, and its occupancy on\n                    <jats:italic>Th<\/jats:italic>\n                    promoter encompassing ER81 binding site is established, finally culminating in desired TH expression. Together, these findings reveal a unique ZIC3-mediated bimodal regulation of TH in OB and MB derived neurons.\n                  <\/jats:p>","DOI":"10.1038\/s41420-025-02448-2","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T10:21:57Z","timestamp":1744366917000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Zic3 enables bimodal regulation of tyrosine hydroxylase expression in olfactory bulb and midbrain-derived neurons"],"prefix":"10.1038","volume":"11","author":[{"given":"Smitha","family":"Bhaskar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeevan","family":"Gowda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Hegde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya Chandra Rao","family":"Thumu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreetama","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"M Bellchambers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendrakumar","family":"Ramanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma Merchan","family":"Sala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Ware","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyothi","family":"Prasanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-1985","authenticated-orcid":false,"given":"Anujith","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"2448_CR1","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1002\/cne.21205","volume":"501","author":"S Parrish-Aungst","year":"2007","unstructured":"Parrish-Aungst S, Shipley MT, Erdelyi F, Szabo G, Puche AC. 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