PRIMORDIAL FOLLICLE ENDOWMENT AND REPRODUCTIVE AGING

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Female mammals are born with a non-replenishable stockpile of oocytes that is gradually depleted over time. The long-range objective of this work is to determine whether a change in size of the original endowment of oocytes will affect the duration of the fertile lifespan and reproductive competence during the fertile years. The original number of oocytes is determined by two events that occur during the embryonic period: germ cell proliferation and germ cell death. Mitosis of germ cells generates a vast population of oogonia but this population is immediately reduced by a massive wave of apoptosis that occurs during the final days of embryonic life. The specific aim of this application is to test the hypothesis that overexpression of BCL-2 in the oogonia will reduce germ cell loss during the embryonic period, producing a surfeit of primordial follicles in the neonatal mouse. Transgenic mice will be produced that carry the human BCL-2 gene, controlled by the c-kit promoter. Overexpression of the "survival gene" BCL-2 has been shown to prevent apoptotic cell death in other tissues. c-kit is expressed abundantly by the germ cells just prior to their massive wave of degeneration. Thus, the germ cells of these transgenic mice should contain very high concentrations of BCL-2 at the very time when they would be most likely to undergo apoptosis. This may prevent apoptosis, leading to enhanced survival of germ cells and resulting in an over- endowment of primordial follicles. Ovaries of the transgenic mice will be evaluated by histological morphometry shortly after birth to determine if they contain a greater-than-normal number of oocytes. The experiment proposed in this application has the potential for generating a transgenic animal model that will be invaluable for studying a wide range of questions concerning the primordial follicle stockpile.