In the past 10 years, the incidence of male infertility cases has increased at an alarming rate resulting in development of a new syndrome- Testicular Dysgenesis Syndrome. The increase in testicular abnormalities is not understood but may be a direct result of genetic or environmental disruption of cell differentiation during testis morphogenesis. Formation of cords, and sex-specific vascular, are the two morphological hallmarks that distinguish the testis from the ovary. Testis development is initiated by Sertoli cell differentiation and expression of Sry, causing mesonephric cell migration. Removal of the mesonephros or blockage of mesonephric cell migration prevents cord formation. Thus, the migration of mesonephric derived cells, which include pre-endothelial and pre-peritubular cells, are critical to testis development. The objective of this proposal is to identify Vascular Endothelial Growth Factor (VEGF) mediated mechanisms that induce endothelial cell migration and sex-specific vascular development in the testis. Recently, we have shown that inhibition of VEGF arrested both vascular development and cord formation suggesting that these two events are interdependent. Furthermore, we also have identified a potential mechanism in which altered ratios of VEGF angiogenic and inhibitory isoforms may result in sex-specific regulation of endothelial cell migration. Therefore, the central hypothesis for this proposal is that VEGF-mediated stimulation of signal transduction cascades regulates both sex-specific vascularization and seminiferous cord formation in the testis. To test the central hypothesis and accomplish the overall objective of this application the following three specific aims are proposed: 1) Determine if modulators of VEGF signal transduction result in sex-specific endothelial cell migration during gonadal morphogenesis; 2) Determine if Growth Factors that stimulate or nhibit the SMAD signal transduction pathway regulate ratio of VEGF angiogenic and inhibitory isoforms during gonadal morphogenesis; 3) Determine the in vivo effects of Sertoli cell specific VEGF loss on gonadal unction and morphogenesis. The results obtained from this proposal will greatly aid in identifying critical details involved in the process of testicular morphogenesis, a prerequisite for uncovering development-based origins of male infertility leading to Testicular Dysgenesis Syndrome. ? ? ?
