Molecular aspects of female and male gonadal development in mammals

In mammals, the choice between male or female development is genetically determined. Sex determination takes place when the embryonic gonad becomes either a testis or an ovary. This process is directed by genes that have been discovered by genetic analysis of sex-reversed patients and confirmed by knock-out experiments in mice. The testis-determining pathway is better known than the ovary pathway. SRY, a gene located on the Y chromosome, triggers a complex genetic cascade leading to testicular differentiation. In this cascade, two genes play a crucial role in male differentiation, SOX9 and FGF9, which contribute to testicular cord formation. However, only a minority of 46,XY sex-reversed patients can be explained by mutations in known genes such as SRY, SOX9, WT1 and SF1, suggesting that other genes influencing sex determination are yet to be discovered. In females, some rare genes that induce ovarian failure or female-to-male sex-reversal, have been found through gene-targeted inactivation in mice or positional cloning of mutations in humans and goats. In both sexes, genetic analysis of sex-reversed individuals (XX males, XX and XY hermaphrodites and XY with complete or partial dysgenesis) remains an approach of choice to isolate new genes involved in sex determination.