TGFβ1 Role in the Fine Balance of Ovulation

The ovary homes the oocyte reservoir, each protected and nourished by somatic granulosa and theca cells, comprising the follicle. Folliculogenesis, the process of follicle development, culminating in ovulation, is subjected to regulation by members of TGFβ family. Even though documented that TGFβ1 is involved in the early follicular phase and corpus luteum regression, its precise role in ovulation remains unclear. We hypothesize that TGFβ1 acts as an upstream regulator of the FSH-LH axis. We set to elucidate TGFβ1 role by utilizing different transgenic mice models. In one such mouse model an extracellular inhibitor of TGFβ1, Vasorin, is deleted exclusively in the granulosa cells (GCs) of growing follicles, resulting in a higher availability of TGFβ1 in the GCs extracellular environment (Vasn cKO). In addition, we established a TGFβR2 cKO mouse in which a genetic inhibition of TGFβ1 is achieved by specifically deleting TGFβR2 in GCs of growing follicles. We show that in Vasn cKO mice, the number of FSHR and LHR expressing follicles is higher. Moreover, the number of expended cumulus-oocyte complexes in response to hCG is larger, resulting in a two-fold increase of ovulated oocytes. Furthermore, in TGFβR2 cKO, the number of LHR presenting follicles is reduced and the ovulatory response is diminished. Interestingly, a reduced vasculature network around antral follicles is noticed. Remarkably, TGFβR2 cKO mice present higher gravidity rate, manifested by a higher number of pups per litter. Our results so far, place TGFβ1 as a positive up-stream regulator of FSHR, thus augmenting the ovulatory response.