T-box transcriptional control of Drosophila wing development

How do T-box transcription factors regulate target gene expression to control the formation and maintenance of our body parts? T-box family members are related through a similar DNA binding domain, which determines how these proteins interact with specific DNA sequences; the shared DNA binding domain means that these proteins can bind to the same DNA sequences in the regulatory regions of target genes leading to a potential competition. T-box proteins can have different activities: activation or repression of target genes, with some having both activities. We hypothesize that the interaction of T-box factors in the same cell ultimately defines which target genes are expressed and their expression levels. We will characterize how T-box factors modulate gene expression in the developing wing of the fruit fly, which develops in a similar fashion to the human forelimb. We will take advantage of the exquisite genetic tools in the fly to identify changes in gene expression upon ectopic expression of mouse T or Tbx6, in addition to gene expression changes upon ectopic and knocked-down expression of endogenous fly T-box factors. These studies are an important first step in identifying pathways that are affected in mutant situations, ultimately explaining the observed fly wing phenotypes. Development in humans is extremely sensitive to the levels of these T-box proteins; human congenital disorders affecting multiple tissues, including the limb, result from mutations in just one of the two copies of specific T-box genes. In addition, their overexpression can lead to cancers. Understanding the activity of these transcription factors and the identification of their target genes will contribute to our understanding of how T-box factors influence various human syndromes and cancers when they are under-, over- or ectopically expressed