The Nuclear Receptor Nr5a2 Coordinates Ovulation and Female Fertility in Granulosa Cells of Different Stages of Follicle Maturation in Mice.

Abstract

The nuclear receptor Nr5a2 (liver receptor homolog-1) is expressed in the ovary, exclusively in granulosa and luteal cells. Germline ablation of Nr5a2 causes embryo lethality, while conditional disruption beginning with the primary follicle stage by means of Nr5a2-floxed and Amhr2Cre/+ mice results in failure of ovulation and luteinization. We hypothesized that Nr5a2 modulates the events leading to development of a preovulatory follicle and its consequent ovulation in a temporal sequence. To test this, granulosa-specific mutants (hereafter characterized as Nr5a2gc-/-) were generated by crossing Nr5a2-floxed mice with mice expressing the Cyp19-Cre, thereby excising Nr5a2 at the antral (tertiary) follicle stage. Similar to Amhr2-Cre driven disruption of Nr5a2, no litters were born to Nr5a2gc-/- females, while Nr5a2gc+/+ females were fertile (six-month breeding trial; n = 5 per genotype). In contrast to Amhr2-Cre driven disruption of Nr5a2, the pattern of estrous cyclicity and serum progesterone appeared to be normal in Nr5a2gc-/- mice compared to Nr5a2gc+/+ mice (n = 5). Likewise, ovarian morphology indicated that antral follicles were present but that cumulus expansion was distinctly absent in Nr5a2gc-/- follicles. In further contrast to Amhr2-Cre driven disruption of Nr5a2, Nr5a2gc-/- ovaries in our study had corpus luteum-like structures that appeared to be comprised of luteinized theca cells surrounding degenerating granulosa cells. Entrapped oocytes were found within these structures. Thus, it was apparent that interdiction of Nr5a2 expression using Cyp19Cre/+ in antral follicles enabled further maturation of follicles than did excision by Amhr2 Cre/+. It also allowed the development of a luteal-like structure in the absence of ovulation. We conclude that Nr5a2 differentially regulates ovarian folliculogenetic and ovulatory processes in granulosa cells of small and antral follicles. Supported by CIHR grant FRN 11018. (poster)