{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:10:15Z","timestamp":1785409815648,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R15CA249617"],"award-info":[{"award-number":["1R15CA249617"]}]},{"award":["1R15CA249617"],"award-info":[{"award-number":["1R15CA249617"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Arizona State University, Barrett the Honors College"},{"id":[{"id":"https:\/\/ror.org\/03efmqc40","id-type":"ROR","asserted-by":"publisher"}]},{"name":"New College Undergraduate Inquiry and Research Experiences"},{"name":"School of Life Sciences Undergraduate Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25D), produced primarily in the kidney, acts in numerous end-organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis, immune responsiveness, and aspects of behavior. Tyrosine hydroxylase (TH) encodes a neuronally expressed enzyme that catalyzes the initial, rate-limiting step in the production of several catecholamine neurotransmitters and hormones, including dopamine, norepinephrine, and epinephrine. Herein we report that TH mRNA is significantly induced (2.5-fold) and NURR1 mRNA is induced 9.3-fold by 10 nM 1,25D in differentiated human SH-SY5Y neuroblastoma cells. Similar results were observed in human U87 glioblastoma cells (TH, 2.6-fold; NURR1, 3.6-fold). Comparative analysis of TH gene promoter-proximal sequences from human, mouse, and rat identifies candidate NURR1-responsive elements (NBREs) at the following positions: \u221235, \u2212855, \u22121470, and \u22122343 bp in the human gene; \u221234 and \u2212961 bp in the mouse gene; and \u221234, \u2212350, and \u2212873 bp in the rat gene, consistent with NURR1 acting as a recurring regulatory factor at TH promoters across mammalian species. Furthermore, by interrogating VDR ChIP-seq\/cistrome datasets, we identified candidate vitamin D-responsive elements (VDREs) at the human NURR1 locus that provide a plausible genomic framework for direct regulation of NURR1 by 1,25D\/VDR. We propose that 1,25D-liganded VDR acts as a primary inducer of NURR1, which in turn secondarily activates expression of the TH gene, thereby defining a transcriptional route through which 1,25D\/VDR signaling may influence TH-linked dopaminergic gene programs. Retinoid X receptor (RXR) may facilitate both NURR1-dependent and -independent potentiation of TH transcription because the rexinoid, bexarotene, significantly enhances TH mRNA in human U87 cells, either alone (2.0-fold) or in combination with 1,25D (4.1-fold). In addition, bexarotene and its novel analogs, A41 and A55, induce NURR1 mRNA expression in U87 cells by 2.8-, 3.1-, and 4.8-fold, respectively, with A55 outperforming the parent compound at matched concentration. Because Parkinson\u2019s disease is characterized by the selective degeneration of dopaminergic neurons and impaired NURR1-dependent transcriptional programs, our findings identify a 1,25D\/VDR\u2013NURR1\u2013RXR transcriptional axis as a previously underappreciated regulatory framework for studying TH gene expression and dopaminergic gene regulation in Parkinson\u2019s disease-relevant neural contexts.<\/jats:p>","DOI":"10.3390\/cells15131210","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T07:59:47Z","timestamp":1783065587000},"page":"1210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["1,25-Dihydroxyvitamin D Induces a NURR1\u2013Tyrosine Hydroxylase Transcriptional Axis Modulated by Rexinoid\/RXR Signaling in Parkinson\u2019s Disease-Relevant Human Neural Cell Models"],"prefix":"10.3390","volume":"15","author":[{"given":"Michael A.","family":"Sausedo","sequence":"first","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanchita","family":"Mallick","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhela L.","family":"Sabir","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Livingston","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quang T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mobin Emran","family":"Doost","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Arizona, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl E.","family":"Wagner","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-4368","authenticated-orcid":false,"given":"Pamela A.","family":"Marshall","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8360-3066","authenticated-orcid":false,"given":"Carol A.","family":"Haussler","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Arizona, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Haussler","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Arizona, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-9161","authenticated-orcid":false,"given":"Peter W.","family":"Jurutka","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"},{"name":"College of Medicine, University of Arizona, Phoenix, AZ 85004, USA"},{"name":"John Shufeldt School of Medicine and Medical Engineering, Arizona State University, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e10419","DOI":"10.1002\/jbm4.10419","article-title":"Vitamin D: Brain and Behavior","volume":"5","author":"Eyles","year":"2021","journal-title":"JBMR Plus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6048","DOI":"10.3390\/nu6126048","article-title":"Neurochemical effects of chronic administration of calcitriol in rats","volume":"6","author":"Jiang","year":"2014","journal-title":"Nutrients"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.mce.2017.05.035","article-title":"Vitamin D and the brain: Genomic and non-genomic actions","volume":"453","author":"Cui","year":"2017","journal-title":"Mol. 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