The overall goal of this proposal is to understand the function of the EGF network during the LH-induced ovulatory process. Preliminary studies from our laboratory indicate that three members of the EGF-like growth factor family (epiregulin/EREG, amphiregulin/AREG, and betacellulin/BTC) are induced by LH at the time of ovulation and that exogenous application of these factors to cultured follicles recapitulates several effects of LH, including oocyte resumption of meiosis and cumulus expansion. In addition, an indispensable role of EGF receptor signaling in LH action during ovulation is suggested by pharmacological and preliminary genetic studies. On the basis of these findings, we propose the hypothesis that LH regulation of the EGF network is critical for the ovulatory process. Studies to test this hypothesis are organized into three specific aims. With the first specific aim, we will investigate the impact of ablation of several genes of the EGF network on the ovulatory process in vivo. Mice with deletion of the AREG or EREG gene and with compound mutations affecting a ligand and the EGF receptor will be studied for reproductive phenotypes. With the second specific aim, the synthesis and processing of EGF-like growth factors, as well as the regulation of their secretion, will be investigated in in vitro models of granulosa cells and intact follicles. The third specific aim will be devoted to understanding how EGF receptor signaling is integrated in the signaling cascades activated by gonadotropins during the periovulatory period. These studies will contribute to our understanding of the physiology of ovulation, a process critical for fertility. They will also provide the rational basis to design pharmacological strategies to manipulate fertility or to improve culture conditions for in vitro nuclear and cytoplasmic maturation of oocytes. Finally, a better understanding of the function of EGF-like growth factors will contribute to the understanding of the biology of some tumors of gynecological interest.
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