Regulation of Oocyte Viability by Granulosa Cell Contact

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DESCRIPTION (provided by applicant): Menopause occurs once the number of primordial follicles is depleted. Moreover, a rapid depletion of primordial follicles is associated with the age-related decline in fertility and premature ovarian failure. It has been estimated that about 70% of these follicles are lost because of oocyte death. Other than this, extremely little is known about the mechanism by which these small follicles are maintained. Insight into the survival mechanisms that influence primordial follicles could come from understanding how these follicles are formed. During embryonic development, primordial germ cells (PGCs) migrate into the developing mammalian ovary, proliferate and then enter meiotic prophase. At this stage, many of the PGCs die via a specific pathway known as apoptosis. However, some PGCs establish contact with somatic cells (presumptive granulosa cells) to form primordial follicles. These PGCs, now referred to as oocytes, appear to be protected from undergoing apoptosis. This process occurs in all mammalian species including humans. While it has been known for decades that cell contact seems to protect oocytes from dying, the mechanism through which cell contact promotes oocyte survival is completely unknown. It is known that granulosa cell-oocyte interaction is mediated, in part, by the adhesion proteins, E- and N-cadherin. Based on our previous studies of granulosa cell apoptosis, we propose that E- and/or N-cadherin mediated cell contact stimulates phosphatidylinositol 3 kinase (PI3K) activity within the oocyte. It is further proposed that PI3K ultimately acts to maintain the viability of the oocyte. Understanding how granulosa cells interact with oocytes to preserve oocyte viability could provide important insights into various aspects of infertility and the mechanisms that control entry into menopause. Therefore, we will determine: 1) the effect of granulosa cell contact on the rate at which oocytes undergo apoptosis in vitro; 2) whether E- and/or N-cadherin mediated cell contact regulates oocyte viability; and 3) whether E- and/or N-cadherin mediated cell contact stimulates PI3K activity and thereby maintains oocyte viability.