A wide range of molecules promote nerve growth, and these include cell adhesion molecules (CAMs), NCAM, N-cadherin, and the L1 glycoprotein are CAMs that are normally found on both the advancing growth cone and also on cellular substrates, and in general operate via a homophilic binding mechanism. In recent years it has become clear that nerve growth stimulated by these CAMs does not rely on the adhesion function of these molecules, but instead requires that the CAMs activate second messenger cascades in neurons. A large body of evidence supports the hypothesis that homophilic binding of the CAM in the substrate to the CAM in the neuron leads to activation of the neuronal FGF receptor, possibly via a direct interaction in cis between the CAM and the FGF receptor. The consequential activation of PLC gamma is both necessary and sufficient to account for the neurite outgrowth response stimulated by the above three CAMs. Based on the above model, we reasoned that soluble CAMs might also be able to stimulate neurite outgrowth and that such agents might be developed as potential therapeutic agents for stimulating nerve regeneration. To this end we have made soluble chimeric molecules consisting of the extracellular domain of NCAM or L1 fused to the Fc region of human IgG 1. We have found that these molecules can stimulate neurite outgrowth from rat and mouse cerebellar granule cells cultured on a variety of tissue culture substrates and that they do so by activating the FGF receptor signal transduction cascade in the neurons. Consistent with this model, we find that neurons that have their FGF receptor function ablated as a consequence of the expression of dominant negative FGF receptors, no longer respond to the soluble CAM. Downstream targets of CAM function have also been studied. Addition of soluble CAMs to isolated growth cone preparations from mouse or rat brain leads to enhanced phosphorylation of the GAP-43 protein providing a link between the cell surface and the cytoskeleton.