Role of human SRY and SOX9 in sex determination and disease.

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The decision to develop as a male or female is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. The correct development of these reproductive organs depends on the coordinated activation of a network of genes by transcription factors. Analysis of patients with defective reproductive organs has shown that a number of these individuals have mutations in two transcription factor genes, SRY and SOX9. Mutations in SRY (Swyer syndrome) or SOX9 (autosomal sex reversal-campomelic dysplasia) cause the development of female reproductive structures in individuals with male chromosomes. Towards understanding how SRY and SOX9 work to determine sex, we have identified four proteins that interact with SRY and SOX9. Two of these proteins, called importin-beta and calmodulin have a role in transporting SRY and SOX9 into the cell nucleus. The other two proteins, called PC4 and HSP70, appear to be involved in co-operating with SRY and-or SOX9 to turn genes on. In the developing mouse testis, a large number of genes are expressed at the time immediately following the expression of SRY and SOX9. We will identify which of these 50 genes are being directly switched on or off by SRY and SOX9 during sex determination. These studies will identify how SRY and SOX9 direct normal testis formation and how mutations cause developmental defects. Also, by unravelling the testis formation pathway, we expect to identify new genes involved in sexual dysmorphology syndromes.