A HUMAN HOMOLOG OF THE DROSOPHILA SEX DETERMINATION FACTOR TRANSFORMER-2 HAS CONSERVED SPLICING REGULATORY FUNCTIONS

Regulation of gene expression through alternative pre-mRNA splicing ap pears to occur in all metazoans, but most of our knowledge about splic ing 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) prote in, directs sex-specific splicing of pre-mRNA from the sex determinati on gene doublesex (dsx). Here we report the identification of htra-2 a lpha, a human homologue of tra-2. Two alternative types of htra-2 alph a cDNA clones were identified that encode different protein isoforms w ith striking organizational similarity to Drosophila tra-2 proteins, W hen expressed in flies, one hTRA-2 alpha isoform partially replaces th e function of Drosophila TRA-2, affecting both female sexual different iation and alternative splicing of dsx pre-mRNA. Like Drosophila TRA-2 , the ability of hTRA-2 alpha to regulate dsr is female-specific and d epends on the presence of the dsx splicing enhancer, These results dem onstrate that htra-2 alpha has conserved a striking degree of function al specificity during evolution and leads us to suggest that, although they are likely to serve different roles in development, the tra-2 pr oducts of flies and humans have similar molecular functions.