Unmasking a role for sex chromosomes in gene silencing.

In mammals, the primary step in male sex determination is the initiation of testis development in the bipotential gonad primordium. This step depends on the Y-linked male sex-determining gene, Sry. Expression of Sry in the XY gonad, or as a transgene in an XX gonad, leads to the differentiation of Sertoli cells. Failures in Sertoli cell differentiation in the XY gonad result in sex reversal and ovary formation. In addition to Sertoli cell differentiation, we are studying the signaling pathways between Sry expression and early steps in testis organogenesis using mouse as a model system. Using genetic and cell biology approaches, we determined the origin of several key cell types of the testis. We also identified two pathways, proliferation and cell migration, that are controlled by Sry and lead to the architectural patterning of the testis. Currently we are investigating the novel hypothesis that reciprocal signals between the vasculature and Sertoli cells are involved in patterning testis cords. Testis organogenesis is an ideal model system to study the integration of vasculature during development of organ structure. In addition, we are investigating critical signals between Sertoli cells and germ cells during testis cord formation. Defects in these signals result in teratomas and gonadal blastomas, common neoplasias in young boys. Experimental approaches include the use of molecular and biochemical techniques, mutant mice, transgenics, organ culture assays, differential screens, immunocytochemistry imaging techniques, and classic mouse genetics.