Granulosa cell expression of Fos is critical for regulating ovulatory gene expressions in the mouse ovary

Abstract

A previous study showed that female Fos null mice fail to ovulate even when given gonadotropins, suggesting that ovarian expression of Fos is critical for successful ovulation. However, the expression of FOS and function of FOS have not been determined in the mouse ovary. FOS, a member of the Fos family (Fos, Fosb, Fosl1, and Fosl2), functions as a transcription factor by forming a heterodimer complex with a member of Jun family (Jun, Junb, and Jund). This study demonstrated rapid increases in Fos, along with other Fos and Jun family members, after hCG administration in the ovary of immature PMSG-primed mice and after the LH surge in naturally cycling animals. ChIP-seq analysis identified 1965 FOS-binding genes in granulosa cells collected at 3 h post-hCG, including Pgr, Ptgs2, Tnfiap6, and Edn2, genes known to be involved in the ovulatory process. When super-ovulation was induced, the number of oocytes released was significantly reduced in Esr2^cre/+-driven granulosa cell-specific Fos knockout (gcFosKO) mice. This reduction was accompanied by lower expressions of Pgr, Ptgs2, Ptgs1, and Edn2 in preovulatory follicles of gcFosKO mice compared to those in control littermates. In addition, gcFosKO mice showed a trend toward a decreased average litter size. Together, the present study indicates that the preovulatory induction of Fos expression is crucial for increasing the expression of key ovulatory genes, yet the role of FOS may be partially substituted by other Fos and Jun family members induced in the preovulatory follicle in the gcFosKO mouse ovary.