EXPRESSION OF A DOMINANT-NEGATIVE FGF RECEPTOR INHIBITS AXONAL GROWTHAND FGF RECEPTOR PHOSPHORYLATION STIMULATED BY CAMS

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are hemoph ilic binding molecules that stimulate axonal growth. We have postulate d that the above CAMs can stimulate this response by activating the fi broblast growth factor receptor (FGFR) in neurons. In the present stud y, we demonstrate that activation of NCAM and L1 can lead to phosphory lation of the FGFR. Both this and the neurite outgrowth response stimu lated by all three of the above CAMs are lost when a kinase-deleted, d ominant negative form of FGFR1 is expressed in PC12 cells. In addition , we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost t heir ability to respond to NCAM, N-cadherin, and L1. A peptide inhibit or of phospholipase C gamma (PLC gamma) that inhibits neurite outgrowt h stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimul ate axonal growth, and that PLC gamma is a key downstream effector of this response.