The goal of the proposed work is to gain insight into the molecular mechanisms of pattern formation in Drosophila limbs. The research proposed in this application is aimed to answer the following questions: 1) How are wings and legs differently specified? Analyses of lack-of-function and ectopic expression phenotypes of the LIM-homeobox gene dlim1 suggest its involvement in leg versus wing cell fate choice. They also point to a role of dlim1 in proximal leg domain specification. The function of dlim1and its genetic interactions with other leg and wing patterning genes will be investigated using mosaic analysis, and other genetic and molecular approaches. 2) How is apterous regulated to the presumptive dorsal wing? A dorsal wing apterous enhancer has been identified. This enhancer is conserved in the mouse apterous orthologue (mlhx2). A candidate gene approach employing mosaic analysis, in vitro DNA binding assays, site directed mutagenesis and transgenic analysis would be used to identify the regulators. 3) What genes mediate signaling from the ventral compartment to activate Notch at the dorso-ventral boundary? We hypothesize that the gene clipped is involved in dorsoventral patterning and mediates signaling to Notch from the ventral compartment. To test this hypothesis the Clipped protein product will be identified, and its function will be investigated in cell culture and in genetic mosaics to determine whether or not it functions cell autonomously. The understanding of the normal functions of Drosophila limb patterning genes, and the identification of the genetic and signaling pathways in which they participate is directly relevant to public health. Many of these genes are implicated in human developmental malformations and in an increasing number of human diseases. These include different types of cancer, stroke and dementia.
