A human homologue of the Drosophila sex determination factor transformer-2 has conserved splicing regulatory functions

Regulation of gene expression through alternative pre-mRNA splicing appears to occur in all metazoan, but most of our knowledge about splicing regulators derives from studies on genetically identified factors from Drosophila. Among the best studied of these is the transformer-2 (TRA-2) protein which, in combination with the transformer (TRA) protein, directs sex-specific splicing of mRNA from the sex determination gene doublesex (dsx). Here we report the identification of htra-2α, a human homologue of tra-2. Two alternative types of htra-2α cDNA clones were identified that encode different protein isoforms with striking organizational similarity to Drosophila tra-2 proteins. When expressed in flies, one hTRA-2α isoform partially replaces the function of Drosophila TRA-2, affecting both female sexual differentiation and alternative splicing of dsx pre-mRNA. Like Drosophila TRA-2 the ability of hTR-2α to regulate dsx is female-specific and depends on the presence of the dsx splicing enhancer. These results demonstrate that htra-2α has conserved a striking degree of functional specificity during evolution and leads us to suggest that, although they are likely to serve different roles in development, the tra-2 products of flies and humans have similar molecular functions.