Greater than 99.9% of ovarian follicles undergo atresia during reproductive life and up to 75% of male germ cells degenerate during the spermatogenic process. Because the maintenance of optimal gonadal function depends on the survival of a limited number of selected follicles and healthy male germ cells, analysis of the hormonal control of gonadal cell demise is important for our understanding of gonadal physiology. We recently have demonstrated that apoptosis is the mechanism underlying follicle atresia and testis cell degeneration. We have devised a sensitive DNA 3'-end labeling autoradiographic method to quantitate apoptosis and have adapted an in situ method to identify the specific cell types involved in apoptosis. Using the rat as a model, we propose to document follicle and oocyte demise throughout ovarian development as well as to study the role of gonadotropins, GH and growth factors in the control of follicle atresia in vitro and in vivo. In the rat testis, we will analyze somatic and germ cell death during development. We will also elucidate the role of gonadotropins, androgens, GH and IGFI in the regulation of testis cell demise. The effect of elevated temperature on germ cell death will be analyzed in cryptorchid testis. To study the molecular mechanism underlying atresia, selected regulation of mRNA levels for different ovarian genes will be monitored during induction of apoptosis and a transgenic mouse model will be developed to suppress follicle atresia by targeted expression of the apoptosis suppressor gene, bcl-2, in the granulosa cells. Studies on the hormonal control of ovarian and testis cell death should provide a better understanding of gonadal physiology and future strategies for contraception in both sexes. Because different pathological conditions in the ovary (e.g., polycystic ovary syndrome and premature ovarian failure) and testis (e.g., oligo- and azoospermia) are likely due to aberrant regulation of apoptosis, the proposed studies may also provide new treatments for infertility.
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