Grant: Discovery Grants Program - Individual

The vivid colour of flowers, the green leaves and the multicoloured butterfly wings seen in a garden are the outcome of one of the most fundamental processes in Biology; the control of gene expression. Gene expression is regulated at all points along the pathway that converts the information stored in DNA (genes) into messenger RNA and then active protein. One major mechanism of regulation is the control of the rate of initiation of transcription; the first step in the production of messenger RNA. The rate of transcription is controlled by DNA-binding transcription factors (TFs). For thirty years, I have been studying the TFs Fushi tarazu (FTZ), Proboscipedia (PB) and Sex combs reduced (SCR). These TFs are important for laying out the body plan of Drosophila: FTZ determines the number of segments that form and PB and SCR determine what the segments will look like. These three TFs contain a common DNA-binding domain, the Homeodomain (HD), and are referred to as HOX TFs. HOX TFs have been analyzed for over thirty years, but the mapping of the regions of the protein important for function as a TF has proven difficult. In recent years, my group and other groups have found that HD¬-containing proteins are composed of small peptide motifs that make small contributions to overall activity. This architecture of TF functional organization results in the genetic phenomenon of differential pleiotropy, which is the non-uniform behavior of mutant alleles in a TF locus. The central question often posed in the analysis of TF function is how a TF, like PB, specifically regulates the genes required for the formation of the mouthparts while another TF, like SCR, specifically regulates the genes required for sex comb formation. I found that the foundation of this central question, which assumes specificity of TF function, is incorrect. Recently I described a phenomenon termed phenotypic non--specificity where TFs are just not specific such that multiple TFs can induce or rescue a phenotype. This is similar to another recently described phenomenon of phenotypic convergence where the expression of different combinations of TFs is associated with the same phenotype. I have explained phenotypic non--specificity using a model of limited specificity of TF function and this grant tests some of the central expectations of this model. Drosophila phenotypic non-specificity will be investigated in more depth to refine the properties of TFs that rescue a phenotype. The prediction of cis--element bypass where the TFs that rescue the same phenotype are proposed to use different regulatory sequences will be tested. The patterns of gene expression in cases of phenotypic non-specificity will also be determined. Phenotypic non--specificity may provide important insights into the control of gene expression. Understanding the control of gene expression is important for studies on how a single celled fertilized egg develops into a multicellular organism composed of distinct cell types.