Sex-lethal is a master regulatory gene that controls all aspects of sexual dimorphism in Drosophila melanogaster. It occupies a uniquely central position in a complex, rather well-defined genetic network; indeed, it may be the most immediate site of action of the X/A balance signal which determines sex in Drosophila. It is a genetically complex locus that functions throughout all stages of development. In many important respects, the functioning of Sx1 in sex determination is analogous to that of the bithorax and Antennapedia gene complexes which determine the segmental identity of Drosophila cells. Recently these genes have been found to be homologous to genes in higher vertebrates. Characterization of such regulatory genes, and of mutations therein, seems likely to provide major insights into the mechanisms by which development is genetically programed in higher organisms, including humans, and to provide an understanding of how that programming can be upset by mutation. Sx1 has been the object of extensive genetic and developmental analysis for years. This proposal involves the first direct molecular analysis of the gene. It is designed to determine the level at which Sx1 is regulated and the mechanisms that underlie that regulation. The work should show how a single gene can encode many different product functions, and how its expression can change as a function of developmental stage, sex, and cell type. The study should contribute important new information with respect to the question of how mutations, particularly mobile genetic elements, can decrease or increase gene function. Of special interest is the characterization of a mobile element that dramatically enhances Sx1 transcript levels. The study employs modern recombinant DNA techniques to correlate Sx1 gene structure with transcript structure, in wildtype and in a wide variety of mutant situations. Developmental analysis of the Sx1 trancript pattern in wildtype and mutant individuals, combined with studies that employ P-mediated transformation by various gene constructs, should provide important tests of hypotheses generated from previous studies, and should allow us and assign specific regulatory functions to specific Sx1 transcripts. The possibility of a relationship between Drosophila sex-determining genes and those of other organisms will be explored.
