Abstract for presentation at 11th International Congress of Human Genetics

The mammalian sex determination pathway is chromosomally controlled as XX gonads develop into ovaries and XY gonads develop into testes. On the Y chromosome is the SRY gene which initiates the development of the testis and the male phenotype. In humans, mutations in SRY cause male-to-female sex reversal in XY individuals. SRY is a member of the SOX protein family and contains a highly conserved HMG box which binds DNA in a sequence specific manner in vitro, consistent with a role for SRY acting as a transcription factor. Despite 15 years since the discovery of SRY, its in vivo function has not been established, hampered by the lack of a defined target gene and experimental cell culture systems. Soon after Sry is expressed in the developing XY gonad, Sox9 is up-regulated. Using a novel reporter assay, we investigated the mechanism by which SRY activates a urogenital ridge specific enhancer element of the SOX9 gene. The assay revealed facets of SRY action including defects in SRY clinical mutants (XY females), post-translational modifications of SRY, subnuclear localisation, and co-activators required to activate the SOX9 enhancer. Up-regulation of SOX9 in the testis is a key process of sex determination observed in a wide range of vertebrates, regardless of the presence/absence of SRY. This study is the first to establish a cell-based assay for SRY transcriptional function and to demonstrate, at least in humans, that the role of SRY is to up-regulate SOX9.