To gain a better understanding of NF1 function, the applicants have chosen to study its properties in Drosophila melanogaster, which is an organism amenable to sophisticated genetic analysis and in which genes encoding components of the Ras-mediated signaling pathway have been well characterized. To that end, the applicants have cloned and characterized a highly conserved Drosophila NF1 homolog. Moreover, they have generated a loss-of-function mutation in Drosophila NF1 that causes a significant reduction in size and the also display abnormalities in cell size and in motor coordination. The proposed experiments are to define the function of NF1 at a cellular level by a detailed analysis of the mutant phenotype. Mosaic analysis will be used to determine whether the reduced cell size NF1 mutants is a cell-autonomous defect. The requirement for NF1 in different types of cells will be analyzed. By testing for the ability of NF1 genes bearing specific deletions to rescue the mutant phenotype, functional domains in the NF1 protein will be identified and delineated. Interactions of NF1 with mutations in the Ras1 signaling pathway will be analyzed and will help to determine the function of NF1 in relation to this pathway in vivo. In order to identify genes that interact with NF1 in vivo, a screen will be conducted for mutations that enhance or suppress the phenotype of NF1 mutants. Loci identified will be characterized and ultimately analyzed at a molecular level.
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