Grant: Operating Grant

Secretion of luteinizing hormone (LH) by the pituitary gland increases dramatically at the end of the follicular growth cycle, causing three key events to occur. The first is ovulation, the release of the oocyte from the follicle. The second is cumulus expansion, wherein a layer of cells surrounding the oocyte disperses and becomes entrapped in a viscous matrix that is required for later fertilization. Third, LH 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 the role of LH in these three events is well known, how exactly it exerts these effects remains incompletely understood. Here, we propose that a newly discovered family of signaling molecules known as the WNTs may be key effectors of LH action. Our published and preliminary results have shown that WNT4, WNT5a and WNT11 as well as the WNT receptors FZD1 and FZD4 are induced in follicular cells by LH, and may then serve to mediate ovulation, cumulus expansion and progesterone biosynthesis. This proposal will seek to confirm these preliminary results, in part by studying mice that lack these WNT and FZD genes, in which we expect LH-regulated effects to be compromised or blocked altogether. We will also study the mechanisms whereby WNTs and FZDs transmit their biological signals, and identify the genes that they regulate. Finally, we will study the biological roles of SFRP2 and SFRP4, which may serve to limit or modulate WNT signaling activity. Together, our studies will uncover new information regarding how LH acts, and about the biological roles and mechanisms of action of WNTs. This research should also provide new insight into fertility disorders such as ovulatory failure and luteal insufficiency.