Role of Bcl-x in Murine Spermatogenesis

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DESCRIPTION (provided by applicant): Apoptosis, or programmed cell death, is a biochemical process that is mediated by a concert of cellular proteins including receptor "initiators" (e.g., TNFR tumor necrosis factor receptor superfamily), the mitochondrial-associating Bcl-2 family "mediators" (e.g., Bcl-2, Bax, Bcl-XL), and the protease "executioners" (e.g., caspases). Spermatogenesis can be blocked by the overexpression or deletion of these apoptosis-related genes, leading to male infertility or sterility. For example, ectopic expression of Bcl-2 and Bcl-x in transgenic mice inhibits apoptosis of spermatogonia and causes infertility. In addition, Bcl-x is expressed in the mouse and human testis within spermatogonia and spermatocytes. Due to the embryonic lethality associated with the bcl-x null mutation, it has not been possible to ascertain the role of Bcl-x in gamete development. Preliminary data support the hypothesis that Bcl-x is required to maintain the survival of spermatogonia and spermatocytes during murine spermatogenesis. To address this hypothesis the following specific aims are proposed. Specific Aim 1: Determine whether Bcl-x maintains the survival of spermatogonial cell populations in the mouse testes. To do this, we ablate the bcl-x gene in murine spermatocytes using the Cre-lox system. This approach will reveal the role of Bcl-x in spermatocyte survival in the mouse testis. Specific Aim 2: Determine whether Bcl-x and Bax are antagonists in the fate determination of the spermatogonial cell populations in the mouse testes. To do this, we will generate double mouse mutants that lack both the bcl-x and bax genes derived from Cre-lox (bcl-x) and conventional (bax) gene knockout strategies. Resultant mutants will demonstrate whether Bcl-x and Bax compete in determining the apoptotic fate of spermatocytes during murine spermatogenesis.