The human sex-determining gene SRY is a direct target of WT1

The product of the Wilms' tumor gene, WT1, is essential for male sex determ ination and differentiation in mammals. In addition to causing Wilms' tumor , mutations in WT1 often cause two distinct but overlapping urogenital defe cts in men, Denys-Drash syndrome and Frasier syndrome. In this study we inv estigated the regulation of the sex determination gene SRY by WT1, Our resu lts showed that WT1 up-regulates the SRY;gene through the proximal early gr owth response gene-1-like DNA-binding sequences in the core promoter. Mutan t WT1 proteins in Denys-Drash syndrome patients were unable to activate thi s promoter. These mutants did not act in a dominant negative manner, as exp ected over the wild-type WT1 in this promoter. We also found that WT1 could transactivate the endogenous SRY plene, These observations, together with the overlapping expression patterns of WT1 and SRY in human gonads, led us to propose that WT1 regulates SRY in the initial sex determination process in humans and activates a cascade of genes ultimately leading to the comple te organogenesis of the testis.