Grant: Operating Grant

Oocytes develop and mature in the ovary within structures called follicles. Follicles are recruited from a reserve and grow under the influence of follicle-stimulating hormone (FSH) produced by the pituitary gland. Once terminally developed, the follicle ruptures to release the (now mature) oocyte at the moment of ovulation. Ovulation itself is triggered by a second pituitary hormone, luteinizing hormone (LH), which also causes the reorganization of the ovulated follicle into a new glandular tissue termed the corpus luteum, which secretes the large amounts of progesterone necessary for the establishment and maintenance of pregnancy. Whereas we have long known FSH and LH to be major players in ovarian follicle development, how exactly they exert their effects remains incompletely understood. Ourselves and others have recently found that a signaling pathway called Hippo is inactivated during FSH-mediated follicle growth, but is rapidly activated during LH-mediate ovulation/luteinization, suggesting that FSH and LH exert their effects, at least in part, via Hippo signaling. This proposal will seek to confirm these preliminary results, in part by studying mice that lack the Hippo pathway genes Yap, Taz, Lats1 and Lats2, in which we expect defects in FSH- and LH-mediated ovarian processes. We will also study the mechanisms whereby Hippo transmits biological signals, and identify the genes that it regulates. Together, our studies will uncover new information regarding how FSH and LH act, and about the biological roles of Hippo signaling in the ovary. This research should also provide new insight into fertility disorders such as ovulatory failure and luteal insufficiency.