This research proposal is directed toward understanding neuron-glia signals involved in myelination. A candidate molecule in the neuron-glia interaction is neuropathy target esterase (NTE), an integral membrane protein present in many neuronal cell types in vertebrates. That NTE is likely to be involved in neuron-glia interaction is suggested by the phenotype of the Drosophila NTE mutant. Errant expression of the NTE gene (called Swiss Cheese, sws) in Drosophila leads to aberrations in axon wrapping by glia, decreased glial cell number and neuronal cell death. The molecular mechanisms leading to NTE mediated cell death are not known. In vertebrates, NTE has been identified as the molecular target for organophosphates that cause neuropathy by inhibiting NTE?s esterase activity. Neither the cellular mechanisms nor the effect on neighboring glia, however, has been examined. So, although a physiological function for NTE has not been determined, there is evidence suggesting a role (either direct or indirect) in neuron-glia interaction. The focus of this proposal is to discover NTE?s role(s) in neuron-glia interactions in vertebrates. The working hypotheses of this proposal are: (1) NTE expresston is regulated in retina and optic nerve during myelination, (2) NTE activity is required for a specific stage of myelination (initiation, active myelination or maintenance of myelin structure), and (3) the molecular domains of NTE activate intracellular pathways that cause changes in the neuron that affect neighboring glia.