SUN-111 - Conditional Double Knockout of Fos and Junb in the Ovary Results in Anovulation and Infertility in Female Mice

Successful ovulation and subsequent formation of the corpus luteum (CL) is essential for female fertility. These processes require tightly controlled changes in the expression of a myriad of genes. Transcription factors induced in ovulatory follicles play critical roles in regulating the expression of these ovulatory genes. Previous in vivo and in vitro studies have shed light on FOS, a subunit of the AP-1 transcription factor, as a critical transcription factor involved in ovulation and luteal formation in humans and mice. However, conditional deletion of the Fos gene by Esr2-Cre in the ovary only resulted in a modest reduction in ovulation rate, fertility, and expression of key ovulatory genes compared to the control mice. Notably, we observed the rapid and robust induction of FOS (mRNA and protein), along with other Fos and Jun family members, in the ovary following hCG administration or endogenous LH surge. This finding suggests that other members of the Fos and Jun families may compensate for the loss of FOS to sustain ovulation and CL development in mice. To test this hypothesis, we generated multiple conditional Knockout (KO) mouse models, including Esr2-Cre-driven double Fos and Junb KO (dFos;JunbKO), double Fos and Fosb (dFos;FosbKO), double Fosb and Junb (dFosb;JunbKO), single Junb KO (sJunbKO), and single Fosb KO (sFosbKO) mouse lines and evaluated their ovulation and fertility in female mice. Strikingly, dFos;JunbKO mice were infertile and exhibited complete ovulation failure, whereas all other single and double KO mouse lines showed only partial inhibition of ovulation and retained fertility, similar to those observed in conditional single Fos KO mice. To investigate underlying mechanisms by which the deletion of both FOS and JUNB affect the ovulatory process, we examined the ovarian morphology of dFos;JunbKO and littermate control mice collected at 11h (pre-ovulation) and 24h (post-ovulation) after hCG administration. While both control and dFos;JunbKO mouse ovary contained large ovulatory follicles before ovulation, only control mice developed newly forming CLs after ovulation. Meanwhile, dFos;JunbKO ovaries retained unruptured follicles containing entrapped cumulus oocyte complexes. Furthermore, qPCR and in situ hybridization results showed partial reduction in the expression of key ovulatory genes (Pgr, Ptgs2, Edn2) in sFosKO mice, while more pronounced suppression of these genes in dFos;JunbKO mice. Serum progesterone levels also showed a significant reduction in dFos;JunbKO mice at 11, 24, and 48h post-hCG compared to control mice. Taken together, these data indicate that FOS and JUNB play both redundant and unique roles in the ovulatory process. While loss of one subunit can be compensated by other family members, simultaneous loss of both FOS and JUNB is detrimental to gene regulation, ovulation, and fertility. Supported by R01HD096077 and R01HD116429.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*