2003 WHRG Grant Program

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The Role of TNF± in the Regulation of Ovarian Follicular Endowment
Chuck Greenfeld
School of Medicine, University of Maryland, Baltimore

The ovary is essential for both female reproductive and general physiology, as it is responsible for producing the female germ cell (the oocyte) and the sex steroid estradiol. Despite its importance, there is a paucity of information regarding fundamental processes that occur during its development. During prenatal and early neonatal development, several coordinated processes occur in the ovary. These processes include colonization of the genital ridge by primordial germ cells followed by their differentiation into oocytes. Oocytes then undergo multiple rounds of proliferation to reach a peak population size, but are then heavily culled in the process of germ cell attrition, which reduces their numbers to as little as 5% of their peak number. Surviving oocytes then become surrounded by somatic cells to produce primordial follicles, the functional unit in the ovary. These processes, which are together termed follicular endowment, culminate in the establishment of a finite pool of primordial follicles. The size of the primordial follicle pool is related to the reproductive longevity of the female as it is constantly depleted during each reproductive cycle and is nonrenewable. The opposing processes of follicular endowment, i.e. germ cell proliferation followed by death, are tightly regulated and are conserved across mammalian species. There is surprisingly little known about the mechanisms involved in the regulation of the various processes of follicular endowment. Germ cell death during attrition has been demonstrated to occur by apoptosis, and is very important for culling oocytes and for forming a pool of healthy, competent oocytes at birth. The Bcl-2 protein famuly comprises a group of homologous proteins that are intimately involved in the regulation of apoptotic cell death. Members of the Bcl-2 family are expressed in the ovary of all mammals studied to date. Importantly, they are expressed throughout follicular endowment. Recent data from our lab suggest that perturbation in the expression of individual Bcl-2 family members results in altered follicular endowment in the mouse ovary, though the mechanism by which this occurs is not known. Tumor necrosis factor alpha (TNF±) is a protein with ubiquitous expression that has multiple functions, including stimulation of cellular differentiation or apoptosis. TNF± and its receptors are expressed in the mouse ovary beginning just prior to birth. As TNF± has been shown to be capable of inducing cell death in the adult mouse ovary, it is likely that it is similarly capable in the neonatal ovary, and would therefore have a role in the regulation of follicular endowment. In many cell types, members of the Bcl-2 family mediate TNF±-induced apoptosis. Using a variety of molecular biological and histological techniques, this proposal seeks to test the hypothesis that TNF± regulates germ cell death during follicular endowment in the mouse ovary. In addition, the role of the Bcl-2 protein family in TNF± signal transduction in the mouse oocyte will be examined. Results from these studies will add to what little is known about regulation of follicular endowment. In addition, results will benefit research in women's health, as they will be directly applicable to studies of menopause, as well as assisting in the maintenance of oocyte viability during infertility treatment and chemotherapy.