The development of the male gonad is dependent on the function of the sex determining locus (Sry) present on the Y chromosome. It is generally believed that Sry initiates a cascade of gene interactions that transforms an undifferentiated gonad into a testis. In some instances testis differentiation fails even in the presence of a Y chromosome. This """"""""sex reversal"""""""" is present in the human population causing the development of sterile XY females with high incidence of gonadoblastoma and /or malignant germ cell tumors. Understanding the genesis of this phenotype is therefore an important health issue. These studies will also provide an insight into the mechanisms of gonadal development. This proposal addresses the role of Sry in development of the male gonad using the sex reversal XYDO mouse model. In the XYDOM sex reversal, the Y chromosomes of the M. domesticus vary in their ability to induce testes in the strain C57Bl/6. To elucidate the molecular basis of XYDOM sex reversal the P.I. proposes experiments along the following specific aims: 1. Quantify the Sry expression during testis differentiation in XYDOM sex reversed strains to determine if sex reversal results from a delay in initiation and/or suboptimal expression of Sry. 2. Determine if suboptimal Sry mRNA translation contributes to XYDOM sex reversal. 3. Characterize the molecular mechanism by which the oncogene Kit exacerbates XYDOM sex reversal. 4. Characterize the inter-relationship of Mullerian inhibiting substance and XYDOM sex reversal. 5. Generate and characterize immortalized fetal gonadal cell lines and XYSxr embryonic germ cells to complement XYDOM sex reversal studies.
