Grant: Project 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 shown that a class of secreted signaling molecules called SLITs, along with their receptors called ROBOs, are expressed in the ovary in a pattern suggesting their involvement in follicle development. Our preliminary data indicate that, when follicle cells are treated in vitro with SLIT ligand, gonadotropin signaling and action is suppressed. This proposal will seek to confirm these preliminary results, in part by studying mice that lack Slit1, Slit2, Robo1 and Robo2, which we expect to be hyperfertile due to augmented FSH- and LH-mediated signaling processes. We will also study the molecular mechanisms whereby Slit/Robo and gonadotropin signaling interact. Together, our studies will uncover new information regarding how FSH and LH act, and about the biological roles of Slit/Robo signaling in the ovary. Importantly, this research may also identify new and valuable pharmacologic targets that could be exploited in the clinical context, in fields of application as wide-ranging as the treatment of fertility disorders, contraception, and recovery of fertility following chemotherapy.