Understanding the cellular events underlying ovulation and subsequent corpus luteum (CL) formation is critically important because these biological processes provide the foundation of our ability to regulate female fertility. A fundamental cornerstone of the cellular events induced by the preovulatory gonadotropin surge vital for ovulation and CL formation is the expression of specific transcription factors. However, our knowledge of the identity and regulatory actions of gonadotropin-induced key transcription factors remains limited. A recent study has shed light on a member of the activator protein-1 (AP-1) transcription factor family, FOS (a.k.a. c-fos), as a key transcription factor involved in follicular development, ovulation, and luteal formation. Fos-deficient mice failed to ovulate and form CL even when exogenous gonadotropins were administered (1), indicating that the ovarian expression of Fos is necessary for normal ovulation and luteinization. However, little to nothing is known exactly how the FOS/AP-1 transcription factor affects these processes in the ovary. Our preliminary study revealed for the first time that the expression of FOS is highly up-regulated in dominant follicles collected after hCG administration from normally cycling women and in preovulatory follicles after hCG administration in mice. Moreover, we demonstrated that FOS regulated the hCG-induced increase in the expression of key ovulatory genes in human granulosa cells by directly binding to the promoters of these genes. Based on these novel findings, we hypothesized that FOS/AP-1 plays essential roles in ovulation and luteal formation/function both in humans and mice. Fos null mice displayed a pleiotropic phenotype with significant loss of viability at birth. To determine the ovary-specific function/action of FOS/AP-1, we propose to establish novel transgenic mouse models in which Fos expression is ablated in an ovarian cell-specific manner. These mutant mice will be used to assess the ovarian phenotype including follicular development, ovulation, luteal development, and fertility as well as to identify downstream target genes of FOS/AP-1 in ovarian cells (Specific Aim #1). To relate and compare the findings from mice to humans, we will first characterize the spatiotemporally regulated expression of all FOS and JUN family members in ovulatory follicles obtained before and throughout the periovulatory period from normally cycling women. The specific role of FOS/AP-1 in human ovaries will also be determined by identifying downstream target genes of FOS/AP-1 and assessing the cellular impact(s) of FOS' action (Specific Aim #2). The information obtained from the proposed studies will not only advance our understanding of the mechanism necessary for successful ovulation and luteinization but also be instrumental for future translational/clinical application, thus leading to improved management of fertility in vivo and in vitro.
Successful ovulation and subsequent corpus luteum formation and development are essential for female fertility. In the present proposal, we will demonstrate for the first time that the FOS/AP-1 transcription factor plays an essential role in ovulation and corpus luteum formation in both humans and mice. Information derived from the present proposal will provide novel insights into the mechanism(s) underlying ovulation and luteal formation and can be applied for promoting and inhibiting the critical facet of ovarian physiology, thereby allowing us to effectively manage fertility in women.
