title: The orphan nuclear receptor Nr5a2 is essential for luteinization in the female mouse ovary.
abstract: In the ovary, the follicular granulosa cells express the nuclear receptor Nr5a2 (nuclear receptor subfamily 5 group A member 2), also known as liver receptor homolog-1, and after ovulation, Nr5a2 expression persists in the corpus luteum. Previous studies demonstrated that Nr5a2 is required for both ovulation and luteal steroid synthesis. Our objectives were to analyze the temporal sequence in the regulatory effects of Nr5a2 in the ovary, with focus on its contribution to luteal function. We developed a female mouse model of granulosa-specific targeted disruption from the formation of the antral follicles forward (genotype Nr5a2(Cyp19-/-)). Mice lacking Nr5a2 in granulosa cells of antral follicles are infertile. Although their cumulus cells undergo expansion after gonadotropin stimulation, ovulation is disrupted in those mice, at least in part, due to the down-regulation of the progesterone receptor (Pgr) gene. The depletion of Nr5a2 in antral follicles permits formation of luteal-like structures but not functional corpora lutea, as evidenced by reduced progesterone levels and failure to support pseudopregnancy. Progesterone synthesis is affected by depletion of Nr5a2 due to, among others, defects in the transport of cholesterol, evidenced by down-regulation of Scarb1, Ldlr, and Star. Comparison of this mouse line with the models in which Nr5a2 is depleted from the primary follicle forward (genotype Nr5a2(Amhr2-/-)) and after the ovulatory signal (genotype Nr5a2(Pgr-/-)) demonstrates that Nr5a2 differentially regulates female fertility across the trajectory of follicular development.
authors.affiliation: Centre de Recherche en Reproduction Animale (K.B., B.D.M.), Faculté de Médecine Vétérinaire, Université de Montréal, Saint Hyacinthe, Québec, Canada J2S 7C6; Gossen Consultancy (J.G.), 5345 BA Oss, The Netherlands; and Laboratory of Integrative and Systems Physiology (K.S.), École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Kalyne
authors.initials: K
authors.lastname: Bertolin
authors.forename: Jan
authors.initials: J
authors.lastname: Gossen
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Murphy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007247:Infertility, Female / Q000097:blood / Q000378:metabolism / Q000473:pathology; D034461:Luteinization / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010053:Ovary / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C431936:Nr5a2 protein, mouse; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D011980:Receptors, Progesterone; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone