A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation

Abstract

Liver receptor homolog-1 (NR5A2) is expressed specifically in granulosa cells of developing ovarian follicles where it regulates the late stages of follicle development and ovulation. To establish its effects earlier in the trajectory of follicular development, NR5A2 was depleted from granulosa cells of murine primordial and primary follicles. Follicle populations were enumerated in neonates at postnatal day 4 (PND4) coinciding with the end of the formation of the primordial follicle pool. The frequency of primordial follicles in PND4 conditional knockout (cKO) ovaries was greater and primary follicles were substantially fewer relative to control (CON) counterparts. Ten-day in vitro culture of PND4 ovaries recapitulated in vivo findings and indicated that CON mice developed primary follicles in the ovarian medulla to a greater extent than did cKO animals. Two subsets of primordial follicles were observed in wildtype ovaries: one that expressed NR5A2 and the second in which the transcript was absent. Neither expressed the mitotic marker. KI-67, indicating their developmental quiescence. RNA sequencing on PND4 demonstrated that loss of NR5A2 induced changes in 432 transcripts, including quiescence markers, inhibitors of follicle activation, and regulators of cellular migration and epithelial-to-mesenchymal transition. These experiments suggest that NR5A2 expression poises primordial follicles for entry into the developing pool.

Lrh1 can help reprogram sexual cell fate and is required for Sertoli cell development and spermatogenesis in the mouse testis

“…Homozygous null mutations in Lrh1 are lethal due to embryonic arrest [27,28] but heterozygous females are viable and have impaired luteal function and reduced fertility [29]. Conditional deletion of Lrh1 in granulosa cells affects activation of primordial follicles and granulosa cell proliferation and function, and the conditionally mutant females are anovulatory and infertile [19,20,30,31]. In the testis, despite reports of expression in Leydig, Sertoli, and germ cells [17,32], the function of Lrh1 is poorly understood.…”

A screen of repurposed drugs identifies AMHR2/MISR2 agonists as potential contraceptives

“…Moreover, in the mouse ovaries, we uncovered a significant decrease of Nr5a2 , an orphan nuclear receptor specifically expressed in the granulosa cells of all active follicles from the primordial stage forward upon treatment with MIS and all four candidate agonists as seen by qPCR ( SI Appendix , Fig. S4 A ) ( 19 ). In contrast, the expression of the germ cell marker Nobox was unchanged by treatment with any of the candidates or MIS, as analyzed by qPCR, suggesting that the abundance of germ cells was unaffected by those drugs ( SI Appendix , Fig.…”

Pregranulosa cells upregulate cardiac troponin I Tnni3 upon cell cycle resumption during primordial follicle activation.

“…The number of clusters per cell type were as follows: five granulosa cell clusters, six mesenchymal clusters, one oocyte cluster, two epithelial clusters, one immune cluster, two blood cell clusters and one cluster unable to be identified (labelled ‘other’). Granulosa cells were identified by the expression of Fst, Amhr2, Kitl, Runx1, Foxl2, Hmgcs2 and Lgr5 and clusters were labelled as Gc_1 to Gc_5 (Bagheri-Fam et al, 2020; Jones & Pepling, 2013; Meinsohn et al, 2021; Nicol et al, 2019; Ottolenghi et al, 2005; Rastetter et al, 2014; Z. Wang et al, 2015).…”

“…Granulosa cells were identified by the expression of Fst, Amhr2, Kitl, Runx1, Foxl2, Hmgcs2 and Lgr5 and clusters were labelled as Gc_1 to Gc_5 (Bagheri-Fam et al, 2020;Jones & Pepling, 2013;Meinsohn et al, 2021;Nicol et al, 2019;Ottolenghi et al, 2005;Rastetter et al, 2014;Z. Wang et al, 2015).…”