Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans

Wnt-4, a member of the Wnt family of locally acting secreted growth factors , is the first signaling molecule shown to influence the sex-determination cascade. In mice, a targeted deletion of Wnt-4 causes the masculinization o f XX pups. Therefore, WNT-4, the human homologue of murine Wnt-4, is a stro ng candidate gene for sex-reversal phenotypes in humans. In this article, w e show that, in testicular Sertoli and Leydig cells, Wnt-4 up-regulates Dax 1, a gene known to antagonize the testis-determining factor, Sry. Furthermo re, we elucidate a possible mechanism for human XY sex reversal associated with a 1p31-p35 duplication including WNT-4. Overexpression of WNT-4 leads to up-regulation of DAX1, which results in an XY female phenotype. Thus, WN T-4, a novel sex-determining gene, and DAX1 play a concerted role in both t he control of female development and the prevention of testes formation. Th ese observations suggest that mammalian sex determination is sensitive to d osage, at multiple steps in its pathway.