Neurite outgrowth induced by a synthetic peptide ligand of neural cell adhesion molecule requires fibroblast growth factor receptor activation

The neural cell adhesion molecule NCAM is involved in axonal outgrowth and target recognition in the developing nervous system. In vitro, NCAM-NCAM bi nding has been shown to induce neurite outgrowth, presumably through an act ivation of fibroblast growth factor receptors (FGFRs). We have recently ide ntified a neuritogenic ligand, termed the C3 peptide, of the first immunogl obulin (Ig) module of NCAM using a combinatorial library of synthetic pepti des, Here we investigate whether stimulation of neurite outgrowth by this s ynthetic ligand of NCAM involves FGFRs. In primary cultures of cerebellar n eurons from wild-type mice, the C3 peptide stimulated neurite outgrowth. Th is response was virtually absent in cultures of cerebellar neurons from tra nsgenic mice expressing a dominant-negative form of the FGFR1. Likewise, in PC12E2 cells transiently expressing a dominant-negative form of the mouse FGFR1, induction of neurites by the C3 peptide was abrogated. These finding s suggest that the neuritogenic effect of the C3 peptide requires the prese nce of functional FGFRs and support the hypothesis that FGFRs are essential in cell adhesion molecule-stimulated neurite outgrowth. The C3 peptide app ears to stimulate neurite outgrowth by specifically activating an NCAM-FGFR -dependent signaling cascade and may therefore be of considerable interest as a tool for the determination of NCAM-dependent neurite out-growth as wel l as a potential drug capable of promoting outgrowth and regeneration of NC AM-responsive axons.