@article{eb7e6766246643bcbc9da21c9489dcd4,
title = "Human dennd1a.V2 drives cyp17a1 expression and androgen production in mouse ovaries and adrenals",
abstract = "The DENND1A locus is associated with polycystic ovary syndrome (PCOS), a disorder characterized by androgen excess. Theca cells from ovaries of PCOS women have elevated levels of a DENND1A splice variant (DENND1A.V2). Forced expression of this variant in normal theca cells increases androgen biosynthesis and CYP17A1 expression, whereas knockdown of the transcript in PCOS theca cells reduced androgen production and CYP17A1 mRNA. We attempted to create a murine model of PCOS by expressing hDENND1A.V2 using standard transgenic approaches. There is no DENND1A.V2 protein equivalent in mice, and the murine Dennd1a gene is essential for viability since Dennd1a knockout mice are embryonically lethal, suggesting that Dennd1a is developmentally critical. Three different hDENND1A.V2 transgenic mice lines were created using CMV, Lhcgr, and TetOn promoters. The hDENND1A.V2 mice expressed hDENND1A.V2 transcripts. While hDENND1A.V2 protein was not detectable by Western blot analyses, appropriate hDENND1A.V2 immunohistochemical staining was observed. Corresponding Cyp17a1 mRNA levels were elevated in ovaries and adrenals of CMV transgenic mice, as were plasma steroid production by theca interstitial cells isolated from transgenic ovaries. Even though the impact of robust hDENND1A.V2 expression could not be characterized, our findings are consistent with the notion that elevated hDENND1A.V2 has a role in the hyperandrogenemia of PCOS.",
author = "Teves, {Maria E.} and Modi, {Bhavi P.} and Rewa Kulkarni and Han, {Angela X.} and Marks, {Jamaia S.} and Subler, {Mark A.} and Jolene Windle and Newall, {Jordan M.} and McAllister, {Jan M.} and Strauss, {Jerome F.}",
note = "Funding Information: Acknowledgments: The CMV-hDENND1A.V2 and Lhcgr-hDENND1A.V2 transgenic mice were generated by the VCU Massey Cancer Center Transgenic/Knockout Mouse Core, which is supported in part with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. Microscopy was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, by funding from the NIH-NINDS Center Core Grant 5 P30 NS047463 and, in part, by funding from the NIH-NCI Cancer Center Support Grant P30 CA016059. Histological preparations were performed by the Virginia Commonwealth University Cancer Mouse Models Core Laboratory, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. Funding Information: Author Contributions: M.E.T. performed experiments, analyzed data, prepared figures for publication, wrote the manuscript; B.P.M. performed experiments; A.X.H. performed experiments and plotted/analyzed data; J.F.S.III performed experiments, plotted/analyzed data and assisted with writing the manuscript; R.K. performed experiments; J.S.M. performed experiments; M.A.S. performed experiments; J.W. performed experiments; J.M.N. assisted in the immunohistochemistry experiments; J.M.M. performed and designed experiments, analyzed data, wrote the manuscript, prepared figures for publication; J.F.S.III designed experiments, analyzed data, wrote the manuscript. All authors have read and agreed to the published version of the manuscript Funding: This research was funded by National Institutes of Health grants U54HD3449 (to J.F.S.III and J.M.M.), R01HD033852 (to J.M.M.), R01HD058300 (to J.M.M.) and R01HD083323 (to J.M.M. and J.F.S.III). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = apr,
day = "1",
doi = "10.3390/ijms21072545",
language = "English (US)",
volume = "21",
journal = "International journal of molecular sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "7",
}