Female development--all by default?

It has been an indisputable fact that the constitu-tive sex in mammalian fetal development is female. Furthermore, a functioning ovary is not required for the female phenotype, whereas a testis is mandatory for male development. More than 50 years after Jost performed experiments in rabbit embryos in which castration was followed by testis engraftment, his observations remain a beacon of clarity illuminating the mechanism of fetal sexual differentiation — the physical phenotype consistent with male or female sex. 1 Another indisputable fact of mammalian fetal sexual development is the morphogenesis of a bi-potential gonad in the genital ridge, dual internal genital ducts, and a common anlagen for the external genitalia. So what factors determine sexual di-morphism? Clearly, the production of an XY zygote at fertilization is the simplest explanation for the development of a bipotential gonad into a testis. The production of müllerian inhibiting substance by Sertoli cells and androgens by Leydig cells in a critical -concentration–dependent and time-dependent manner induces male sexual differentiation by means of a hormone-dependent process. In contrast , a panoply of genes are involved in gonadal development and, hence, sex determination. 2 There is compelling evidence that a gene on the short arm of the Y chromosome close to the pseudo-autoso-mal region — called SRY , for the sex-determining region of the Y chromosome — is the key player in testis development. The translocation of SRY to the X chromosome during paternal meiosis explains testis development in 90 percent of XX males. Mutations in SRY are present in 10 to 15 percent of XY females who have complete gonadal dysgenesis, and the insertion of the corresponding mouse gene sry into XX mouse embryos results in male offspring. A number of other genes are involved in tes-tis determination, such as SOX9, which is induced by SRY ; steroidogenic factor 1 (SF1); Wilms' tumor 1 (WT1); and DAX1. Perturbations in the structure or function of these genes or their products cause sex-disorder syndromes in humans. More testis-determining genes have been identified through studies in transgenic mice. However, their relevance to disorders such as XY gonadal dysgenesis in humans remains unknown. Are there no key genes for human ovarian determination and differentiation of the female reproductive tract? Some syndromes associated with gene duplication cause XY sex reversal. For instance, the duplication of a 160-kb region on the short arm of the X chromosome (Xp21.3) leads to the development …