This project is directed toward understanding both the mechanism of action and developmental functions of the fringe gene. Fringe was first identified in Drosophila based on its role in controlling growth and patterning in the wing. Multiple fringe-related genes have now been identified in several different animal species, including humans. These fringe genes appear to define a new family of cell-signaling molecules with a unique, boundary-specific, mode of signaling. Mammalian fringe genes are expressed in a wide range of tissues; their expression in neural and hematopoietic tissues is particularly intriguing because of its overlap with the expression and function of members of the Notch signaling pathway. In Drosophila, fringe effects cell fates and induces growth at least in part through regulation of this pathway. Aberrant Notch signaling has been implicated in both murine breast cancer and human acute lymphoblastic T-cell Leukemia. The intersection of fringe with Notch signaling suggests that fringe could be relevant to these cancers. Most of what is known of how fringe functions comes from studies of its activity in a single tissue, the Drosophila wing. In addition, although ultimate molecular responses to fringe signaling have been identified, the immediate targets of fringe remain unknown. This proposal will address these gaps in our understanding of fringe activity in the experimentally amenable system provided by Drosophila melanogaster. To confirm that fringe protein is secreted and to gain insights into its unique boundary-specific action, the cellular and subcellular distribution of fringe protein will be determined by immunolocalization in the Drosophila wing. To determine the different developmental roles that fringe can play, whether its activity is always boundary specific, and whether its signaling is always tied to Notch activity, fringe activity will be investigated in other Drosophila tissue. For these studies the temporal and spatial patterns of fringe activity will be altered by fringe mutation and by mis-expression in transgenic animals. To identify other genes required for fringe signaling, such as the postulated fringe receptor, a genetic screen will be undertaken for mutations that act as dominant enhancers of reduced fringe signaling. Genes identified in this screen will be taken through a battery of tests to confirm their role in fringe signaling, and then analyzed molecularly. Finally, the relationship of fringe activity to the Notch signaling pathway will be investigated in detail using an established cell culture assay.
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