{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:32:42Z","timestamp":1763389962474,"version":"build-2065373602"},"reference-count":72,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["HD065584"],"award-info":[{"award-number":["HD065584"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The Rhox family of homeobox transcription factors comprises established regulators of gonad function, but their downstream targets have been relatively elusive, particularly in the female reproductive tract. Here, we characterize Ins2 as a downstream target of the two granulosa cell-specific factors, Rhox5 and Rhox8, in the ovary. While INS2 is classically produced by islet cells in the pancreas, we found that Ins2 gene expression is present in the mural granulosa cell layer of large antral follicles, and it was not significantly reduced in Rhox5-null mice. This was a surprising finding as we previously validated Ins2 as a direct target of RHOX5 in Sertoli cells, the male counterpart to granulosa cells that serves the germ cell nurse function in the testis. In the ovary, RHOX8 appears to be the major driver of Ins2 expression, as evidenced from the maximal activity of Ins2 promoter reporter plasmids when RHOX8 protein was active within granulosa cells in vitro and the downregulation of endogenous Ins2 in mice with the granulosa cell-specific knockdown of RHOX8 in vivo. RHOX5 induces Rhox8 expression in pre-antral granulosa cells and then becomes relatively silent in peri-ovulatory follicles. However, Rhox8 does not peak until after the ovulatory LH surge. The induction of Rhox8 by progesterone, after the normal window of RHOX5 has passed, may explain why Rhox5-null female mice display apparently normal fertility, if RHOX8 is capable of the redundant stimulation of target genes that are essential for ovulation.<\/jats:p>","DOI":"10.3390\/cells14070478","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T13:48:20Z","timestamp":1742824100000},"page":"478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RHOX Homeobox Transcription Factor Regulation of Ins2 in Rodent Granulosa Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5028-799X","authenticated-orcid":false,"given":"Kanako","family":"Hayashi","sequence":"first","affiliation":[{"name":"Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA"},{"name":"Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3061-150X","authenticated-orcid":false,"suffix":"II","given":"James A.","family":"MacLean","sequence":"additional","affiliation":[{"name":"Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA"},{"name":"Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/humupd\/dmae027","article-title":"New insights into the ovulatory process in the human ovary","volume":"31","author":"Jo","year":"2025","journal-title":"Hum. 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