Grant: Operating Grant

The release of an oocyte at the moment of ovulation is a process that is critical for female fertility. In the ovary, oocytes mature within structures called follicles. Follicle development is tightly regulated by pituitary hormones, as well as by additional factors produced locally within the ovary itself. We have recently discovered that a molecule secreted by follicle cells called WNT4 is required for the later stages of their development. Indeed, the loss of WNT4 results in the accelerated loss of the ovarian follicle reserve in mice, in a manner similar to what occurs in cases of premature ovarian failure in women. Now that we have established the importance of WNT4, the current proposal is aimed at understanding exactly how WNT4 functions. We have shown that WNT4 acts to induce the expression of VEGFA, a hormone also known to promote follicle survival. We aim to demonstrate that VEGFA is a critical mediator of WNT4's follicle survival activity, and to elucidate the mechanism by which WNT4 activates the Vegfa gene. We also believe that the genes Fzd1, Sfrp4 and Rspo1 serve to regulate or potentiate the WNT4 signal, and will seek to prove this by using mice in which these genes have been selectively deleted. Together, our studies will uncover new information regarding how follicles survive and develop until ovulation. This research should also provide new insight into fertility disorders involving follicle development defects, including premature ovarian failure.