The goal of this application is to understand the overlapping functions of Bone Morphogenetic Proteins (BMPs) and to identify the receptors responsible for BMP signal transduction in spermatogenesis. The BMP family regulates numerous aspects of development and differentiation from early embryogenesis and organogenesis to the functional maintenance of a mature organ. The fact that several murine genes encoding BMPs, BMP receptors, and downstream signal transducers are expressed in male germ cells, and Bmp8b null mutants mammalian spermatogenesis. Furthermore, BMP8b null mutants retain partial spermatogenic activity, suggesting that other BMPs may compensate for the loss of BMP8B proteins. In these mutants, any further compromise in the BMP signaling pathway, such as partial loss of other BMPs or BMP receptors may lead to a more severe germ cell degeneration phenotype. Therefore, Bmp8b mutant mice should provide a useful genetic tool to study the functions of these additional genes in spermatogenesis, which will otherwise by difficult to test. Here we propose to determine the functions of Bmp4, Bmp7, and three putative BMP receptors (Alk3, ActRIIA, and ActRIIB) by creating double mutants with Bmp8B and then examining the severity of germ cell deficiency in these mutants. The function of Bmp8a is being investigated by gene targeting and by its ability to rescue Bmp8b mutant phenotype using a transgenic over- expression approach. The results of these genetic studies will add significantly to our understanding of the molecular mechanism controlling mammalian spermatogenesis. Such understanding will lead to novel approaches for the treatment of male infertility, the rescue of endangered species, and methods for increasing the reproductive capacity of farm animals, as well as approaches to birth control.
