SRY, the testis-determining factor found on the Y-chromosome in mice and humans, is one of several Sox family members involved in sexual development. It is known to bind DNA, in support of the proposal that HMG domain proteins act as architectural facilitators for building transcription complexes.
Sassone-Corsi's group thus expected to find Sox proteins colocalized in the nucleus with transcription factors. Instead, SRY and SOX6 proteins associated with splicing factors in nuclear speckle domains. Depletion of SOX6 in HeLa cell extracts blocked splicing of multiple substrates, and expression of the HMG domain only of either SOX6, SOX9, or SRY restored splicing in the extracts, indicating functional overlap of the proteins.
The group's results provide the first association between splicing and sex determination in mammals. The Drosophila genes transformer and sex-lethal encode mRNA splicing factors required for sex determination in flies, indicating that regulated splicing of sex-determining factors may be evolutionarily conserved. According to Sassone-Corsi, to complete the connection “the next step is to identify natural physiological substrates of the Sox and SRY proteins.” He thinks the Sox proteins may control regulated splicing by determining which spliceosomal complexes are formed in different cell types, analogous to the way transcription factors can regulate the basal transcription machinery. ▪
SRY (red) colocalizes with a splicing factor (green) in nuclear speckles.