This project seeks to determine the cellular and molecular basis for the accurate pathfinding ability of embryonic, vertebrate spinal cord motor and sensory neurons. The importance of known cell adhesion-recognition molecules (L1, NCAM, axonin-1/TAG-1, the polysialic moiety of NCAM) on axonal outgrowth will be assessed by perturbing the function of these molecules via in-ovo injection of antibodies or enzymes, and by following up these observations in culture. The signal transduction pathways used and cytoskeletal rearrangements made as growth cones orient to gradients of putative chemotactic substances will be studied in culture. Special effort will be devoted to understanding how the expression of the 5E10 antigen is regulated; the 5E10 monoclonal antibody recognizes a specific phosphorylated state of a cytoskeletal element (probably the middle weight neurofilament subunit) which occurs in growth cones as they detect and respond to specific target derived guidance cues. The importance of this phosphorylation event in pathfinding will be assessed by determining the consequence of misexpression of this antigen. The information to be obtained is relevant to improving neural regeneration and functional recovery following peripheral nerve or spinal cord injury.
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