A MOLECULAR APPROACH TO SEX DETERMINATION IN MAMMALS

Mammalian sex determination occurs in the gonad of the developing embr yo. This process is dependent on the Y-chromosome-encoded Sry gene tha t acts in the somatic cells of the genital ridge. The transient nature of Sry gene expression suggests that it acts as a switch from one cel l fate to another. One of the roles of Sry is to initiate the differen tiation of Sertoli cells, which are the first cell type of the testis to be formed. Two genes are thought to be important in Sertoli cell di fferentiation and function, Sox9, an Sry-related gene, and SF-1, a nuc lear hormone receptor. Sox9 is expressed in Sertoli cells throughout d evelopment of the mouse embryo, and inactivating mutations in this gen e in humans give rise to XY females. SF-1 is also expressed in Sertoli cells and is thought to activate the AMH gene - an early marker of th ese cells. DAX-1, an X-linked member of the nuclear hormone superfamil y, is a candidate for a human condition in which duplication of region s of the X chromosome results in XY females. Expression of this gene d uring mouse development is associated with ovary development and is do wn-regulated in the differentiating testis. Mutations in DAX-1 in huma ns have shown that this gene is not necessary for testis development. The properties of the DAX-1 gene suggest that it is important in ovary determination and might therefore be antagonistic to the action of th e Sry gene.