Neurons extend axons significant distances through the developing embryo to establish the precise and specific patterns of connections essential for nervous system functioning. Recent results implicate receptor tyrosine phosphatases (RPTPs) and tyrosine kinases in axon guidance, indicating that phospho-tyrosine signal transduction might regulate this process. RPTPs often display non-specific phosphatase activity in vitro making biochemical experiments to define substrates and ligands difficult to design. Genetics offers an alternative approach, and Drosophila is an excellent model system in which to investigate this important but understudied protein family, because mutants lacking each of the four known Drosophila axonal RPTPs exist. The proposed research seeks to test the hypothesis that a balance between axon defasciculation mediated by RPTPs and axon bundling involving neural cell adhesion molecules such as Fasciclin II is a crucial component of axon guidance. The first specific aim tests this hypothesis by examining the effects of simultaneously altering the expression of Fasciclin H and the DPTP69D and DPTP99A phosphatases in flies and looking for suppression or enhancement of the axon defects associated with the separate alterations. The second specific aim examines the importance of RPTP phosphatase activity and its regulation in axon guidance. We will test DPTP69D mutants lacking one or both phosphatase domains, an inhibitory motif, or a possible activation motif for their ability to replace the axon guidance and DPTP99A-inhibiting functions of native DPTP69D in vivo, and assay the phosphatase activity of these mutants in vitro. We will use random mutagenesis to make point mutations in order to define other critical structures, and temperature sensitive alleles to determine the temporal requirements for DPTP69D function. The third specific aim seeks to elucidate the biochemical pathway through which the RPTPs control axon guidance by cloning and characterizing a genetically identified member of the DLAR phosphatase signaling pathway. Together these aims should strengthen our understanding of axon guidance, the role of RPTPs in this process, and, through their interaction with Fasciclin II, their involvement in cell adhesion and possibly with tyrosine kinases, two aspects of the potential function of RPTPs as tumor suppressor molecules. Furthermore, conservation of guidance molecules, growth cone receptors and signaling pathways among invertebrates and vertebrates suggests that these efforts will shed light on the establishment of neural circuits in mammals and the potential role of impaired axon guidance in central nervous system disease and mental retardation.
| Song, Jeong K; Giniger, Edward; Desai, Chand J (2008) The receptor protein tyrosine phosphatase PTP69D antagonizes Abl tyrosine kinase to guide axons in Drosophila. Mech Dev 125:247-56 |
| Desai, Chand; Purdy, Joy (2003) The neural receptor protein tyrosine phosphatase DPTP69D is required during periods of axon outgrowth in Drosophila. Genetics 164:575-88 |
