Evaluation of Function-Specific Ligands for the LAR-RPTP and HSPG Syndecan in Neuronal Development

The long-distance signals, cell surface molecules and the extracellular matrix used during intercellular communication are essential for neural development, specifically, cell differentiation and migration, axon outgrowth and target recognition, and synapse formation. Using a bioinformatic approach we compiled a list (The Secretome) of 10,000 Caenorhabditis elegans genes (our library contains ~4,200) that encode for signal peptides, half of which are unclassified. Using RNA interference (RNAi) we have screened for genes that genetically interact with molecules known to regulate the patterning of the nervous system, the leukocyte-common antigen related receptor protein tyrosine phosphatase, LAR (ptp-3) and heparin sulfate proteoglycan, syndecan (sdn-1).We have found that animals lacking either ptp-3 or sdn-1 are largely viable, but double mutants are synthetic lethal (SynLet), indicating they function in parallel pathways. Using this SynLet approach we have isolated 28 molecules that could potentially be ligands with either ptp-3 or sdn-1. We are now analyzing the effect of these 28 molecules on the neural patterning in the DD and VD GABAergic motorneurons, looking for molecules that enhance, suppress, or have no effect on the neural phenotypes seen in ptp-3 or sdn-1.