Neurite outgrowth stimulated by neural cell adhesion molecules requires growth-associated protein-43 (GAP-43) function and is associated with GAP-43 phosphorylation in growth cones

The mechanisms whereby cell adhesion molecules (CAMs) promote axonal growth and synaptic plasticity are poorly understood. Here we show that the neuri te outgrowth stimulated by NCAM-mediated fibroblast growth factor (FGF) rec eptor activation in cerebellar granule cells is associated with increased G AP-43 phosphorylation on serine-41. In contrast, neither NCAM nor FGF was a ble to stimulate neurite outgrowth in similar neurons from mice in which th e GAP-43 gene had been deleted by homologous recombination. Integrin-mediat ed neurite outgrowth was unaffected by GAP-43 deletion. Both neurite outgro wth and rapid phosphorylation of GAP-43 in isolated growth cones required t he first three Ig domains of a NCAM-Fc chimera and were stimulated maximall y at 5 mu g/ml (similar to 50 nM). Likewise, GAP-43 phosphorylation in isol ated growth cones also was stimulated by an L1-Fc chimera. Both neurite out growth and NCAM-stimulated GAP-43 phosphorylation were inhibited by antibod ies to the FGF receptor and a diacylglycerol lipase inhibitor (RHC80267) th at blocks the production of arachidonic acid in response to activation Of t he FGF receptor. Direct activation of the FGF receptor and the arachidonic acid cascade with either basic FGF or melittin also resulted in increased G AP-43 phosphorylation. These data suggest that the stimulation of neurite o utgrowth by NCAM requires GAP-43 function and that GAP-43 phosphorylation i n isolated growth cones occurs via an FGF receptor-dependent increase in ar achidonic acid.