The Orphan Nuclear Receptor Liver Homolog Receptor-1 (Nr5a2) Regulates Ovarian Granulosa Cell Proliferation.
Marie-Charlotte Meinsohn,Fanny Morin,Kalyne Bertolin,Raj Duggavathi,Kristina Schoonjans,Bruce D. Murphy +5 more
TLDR
Nr5a2 is essential for granulosa cell proliferation, but its depletion does not alter the frequency of apoptosis nor autophagy, and in vivo treatment with estradiol-17β failed to rescue decreased proliferation.Abstract:
In mouse ovaries, liver receptor homolog-1 [nuclear receptor subfamily 5, group A, member 2 (Nr5a2)] expression is restricted to granulosa cells. Mice with Nr5a2 depletion in this cell population fail to ovulate. To determine whether Nr5a2 is essential for granulosa cell proliferation during follicular maturation, we generated granulosa-specific conditional knockout mice (genotype Nr5a2 floxed Cre-recombinase driven by the anti-Mullerian type II receptor, hereafter cKO) with Nr5a2 depletion from primary follicles forward. Proliferation in cKO granulosa cells was substantially reduced relative to control (CON) counterparts, as assessed by bromodeoxyuridine incorporation, proliferative cell nuclear antigen expression, and fluorescent-activated cell sorting. Microarray analysis revealed >2000 differentially regulated transcripts between cKO and CON granulosa cells. Major gene ontology pathways disrupted were proliferation, steroid biosynthesis, female gamete formation, and ovulatory cycle. Transcripts for key cell-cycle genes, including Ccnd1, Ccnd2, Ccne1, Ccne2, E2f1, and E2f2, were in reduced abundance. Transcripts from other cell-cycle-related factors, including Cdh2, Plagl1, Cdkn1a, Prkar2b, Gstm1, Cdk7, and Pts, were overexpressed. Although the follicle-stimulating hormone and estrogen receptors were overexpressed in the cKO animals, in vivo treatment with estradiol-17β failed to rescue decreased proliferation. In vitro inactivation of Nr5a2 using the ML180 reverse agonist similarly decreased cell-cycle-related gene transcripts and downstream targets, as in cKO mice. Pharmacological inhibition of β-catenin, an Nr5a2 cofactor, decreased cyclin gene transcripts and downstream targets. Terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling immunofluorescence and quantitative polymerase chain reaction of pro/antiapoptotic and autophagic markers showed no differences between cKO and CON granulosa cells. Thus, Nr5a2 is essential for granulosa cell proliferation, but its depletion does not alter the frequency of apoptosis nor autophagy.read more
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Single-Cell Transcriptomic Atlas of Primate Ovarian Aging.
Si Wang,Yuxuan Zheng,Yuxuan Zheng,Jingyi Li,Yang Yu,Weiqi Zhang,Moshi Song,Zunpeng Liu,Zheying Min,H.X. Hu,Ying Jing,Xiaojuan He,Liang Sun,Lifang Ma,Concepcion Rodriguez Esteban,Piu Chan,Jie Qiao,Qi Zhou,Juan Carlos Izpisua Belmonte,Jing Qu,Fuchou Tang,Fuchou Tang,Guang-Hui Liu +22 more
TL;DR: A comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution is provided, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.
Journal ArticleDOI
The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction
TL;DR: The NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.
Journal ArticleDOI
Nuclear receptors: Key regulators of somatic cell functions in the ovulatory process.
TL;DR: Nuclear receptors are among the panoply of transcriptional regulators with roles in ovulation, and several are necessary for normal ovarian function.
Journal ArticleDOI
Nuclear receptor Ftz-f1 promotes follicle maturation and ovulation partly via bHLH/PAS transcription factor Sim.
TL;DR: Ftz-f1, one of the NR5A nuclear receptors in Drosophila, is transiently induced in follicle cells in late stages of oogenesis via ecdysteroid signaling and its role in regulating Sim expression and follicle cell differentiation can be replaced by its mouse homolog steroidogenic factor 1 (mSF-1).
Journal ArticleDOI
Molecular profiling demonstrates modulation of immune cell function and matrix remodeling during luteal rescue
TL;DR: It is demonstrated that luteal rescue during early pregnancy is mediated by a variety of events, including alteration of immune cell function and matrix remodeling, and that these may be miRNA-regulated.
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TL;DR: The anatomy of the mouse placenta was examined by preparing plastic vascular casts and serial histological sections of implantation sites from embryonic day (E) 10.5 to term to provide important insights into how the fetoplacental unit interacts with the maternal intrauterine vascular system during pregnancy in mice.
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