Sex-determining genes in mice: building pathways

Sry is active in the mouse for a very brief period in somatic cells of the genital ridge to initiate Sertoli cell differentiation. SRY protein must act within the context of other gene products required for gonadal development and must itself act on one or more target genes that will ensure the further differentiation and maintenance of Sertoli cells. Over the last few years several genes have been found that have important roles in gonadal development and sex determination. These include genes encoding transcription factors such as Lhx9, Wt1, Sf1, Dax1, Gata4, Dmrt1 and Sox9, and some involved in cell cell signalling, including Amh, Wnt4 and Dhh. While more await discovery, it is now possible to start putting some of the known genes into pathways or networks. Sox9 probably occupies a critical role in mammals for both the initiation and maintenance of Sertoli cell differentiation. Data will be presented that are consistent with SRY acting directly on Sox9 to ensure its up-regulation. SF1 is also central to gonadal differentiation. Our results imply that it contributes to transcriptional activation of several relevant genes, not just those required for male development, including Sox9 and Amh, but also those that can have an antagonistic effect on Sertoli cell differentiation, such as Dax1. Progress in establishing other regulatory interactions will also be discussed.