This proposal focuses on a set of Drosophila neuronal cell surface signal transduction proteins, the receptor tyrosine phosphatases (RPTPs), which regulate axon guidance and synaptogenesis in embryos, larvae, and pupae. RPTPs are highly conserved between flies and humans, and mammalian RPTPs may also regulate axon guidance and synaptic function. The phenotypes of RPTPs mutations in Drosophila have been examined in detail. However, to understand how RPTPs function in axon guidance, it will be necessary to define their signaling pathways. It is especially important to characterize the ligands and/or co-receptors to which they bind and the substrates on which they act.
Two specific aims of this proposal deal with the analysis of putative RPTP ligands or co-receptors that our group has recently identified, and the third concerns the characterization of candidate RPTP substrates. SAI: We found that the secreted protein Folded Gastrulation (Fog) and the DPTP52F RPTP bind to each other. We now wish to determine if Fog is a ligand for DPTP52F in vivo. We will map the regions of DPTP52F involved in Fog interactions, measure binding affinities, and determine whether Fog affects phosphatase activity. Genetic interaction experiments will be performed to determine if Fog is required for DPTP52F signaling in vivo. SA2: We will study interactions of the DLAR RPTP with the heparan sulfate proteoglycan Syndecan. We identified Syndecan in a novel deficiency screen for genes encoding DLAR binding proteins. Lar and Syndecan (Sdc) mutations display strong genetic interactions, consistent with the hypothesis that Syndecan is required for DLAR function in vivo. We will perform biochemical experiments to measure the affinity of DLAR for Syndecan, map the regions of DLAR involved in Syndecan binding, and determine whether Syndecan affects enzymatic activity. ? ? Further genetic interaction experiments will be conducted in order to determine whether Syndecan is a ? ligand or a co receptor for DLAR. SA3: We identified four candidate RPTP substrates in a modified 2-hybrid yeast screen for clones that interact with 'substrate-trap' mutants of the RPTPs in a phosphorylation dependent manner. We will perform biochemical experiments in transfected cells and transgenic flies to determine whether these are genuine RPTP substrates, and conduct genetic studies to analyze whether they are required for RPTP signaling in vivo. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-2 (02))
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Tagle, Danilo A
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California Institute of Technology
Schools of Arts and Sciences
United States
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