ERM, an ETS Transcription Factor, Is Crucial for Folliculogenesis and Ovulation in Mice.

Abstract

PEA3, ER81, and ERM are members of PEA3 subfamily of ETS transcription factors which are known to influence a host of biological processes. We previously showed that ERM, expressed in Sertoli cells, plays a crucial role in maintaining spermatogonial niche in the mouse testis. However, it is not yet known whether PEA3 family members are expressed in the ovary or play any role in ovarian functions. Here we show that ERM and PEA3 are expressed in mouse ovaries in specific spatiotemporal manners. While PEA3 is expressed in nuclei of granulosa cells prior to ovulation, ERM is expressed during follicular growth at steady-state levels. Both ERM and PEA3 mRNAs are also detected in cumulus-oocyte-complexes (COCs) and in denuded oocytes. Notably, PEA3 is highly expressed in the cumulus cells of ovulated COCs at 16 hr post-hCG. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is critical to oocyte maturation and ovulation. Since several putative ETS-binding sites (EBS) are present in the COX-2 promoter, we examined whether ERM influences COX-2 transcriptional activity. Indeed, we found that addition of ERM increases the transcriptional activity of the 3.2-kb mCOX-2 promoter by 2.5 fold in luciferase reporter assays. The results show that PEA3 and ERM are expressed in granulosa and cumulus cells during folliculogenesis and ovulation, suggesting they influence cellular events in the ovary by regulating downstream genes such as COX-2. In ERM deficient female mice, ovulation is severely impaired even after gonadotropin treatments to induce superovulation. Histological observations revealed that ovaries from wildtype female mice have follicles at various developmental stages with well-formed granulosa cell (GC) layers, while ERM-/- ovaries have smaller follicles with thin GC layers. Even at 16 hr post-hCG which is normally after ovulation, development of follicles in the ERM-/- ovary were halted at preovulatory stages. The results show that ERM, expressed in granulosa and cumulus cells, plays important roles in folliculogenesis and ovulation. We will further perform physiological and molecular evaluations of ERM-/- ovaries and identify ERM target genes in the ovary using gene expression profiling analysis. This research was supported by MOEHRD KRF-2006-312-C00642.