Thomas W. Cline

We are studying how sexual dimorphism in the fruit fly, Drosophila melanogaster, is genetically programmed, how that programming is executed at the molecular level, and how it has evolved. All our work relates in some way to a master developmental switch gene named Sex-lethal, which is the most immediate target of this fly's primary sex determination signal -- the X/A chromosomal ratio. When activated, Sxl imposes female development and the female rate of X chromosome dosage compensation. Male development and dosage compensation ensue when Sxl is inactive. Throughout nearly all of the life cycle, Sxl on/off regulation reflects the operation of a positive feedback loop on Sxl alternative RNA splicing; however, this feedback loop is triggered extremely early in development by a transient effect of X-chromosome dose on Sxl transcription. We are exploiting the unique opportunity that Sxl provides for understanding how RNA binding proteins control gene functioning in vivo and in particular how such proteins regulate RNA splicing. We also are studying how a simple two-fold quantitative change in the dose of genes that comprise the sex determination signal results in an on/off transcriptional response by Sxl. We are exploring the molecular basis for the remarkable differences in somatic versus germline Sxl regulation and functioning. Lastly, we are exploiting the fact that sex determination signals are among the most rapidly evolving aspects of developmental programming to discover how developmental programs evolve.