The Neural Cell Adhesion Molecule (NCAM) plays a crucial role in development of the central nervous system regulating cell migration, differentiation and synaptogenesis. NCAM mediates cell-cell adhesion through homophilic NCAM binding, subsequently resulting in activation of the fibroblast growth factor receptor (FGFR). NCAM-mediated adhesion leads to activation of various intracellular signal transduction pathways, including the Ras-mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)-Akt pathways. A synthetic peptide derived from the second fibronectin type III module of NCAM, the FGL peptide, binds to and induces phosphorylation of FGFR without prior homophilic NCAM binding. We here present evidence that this peptide is able to mimic NCAM heterophilic binding to the FGFR by inducing neuronal differentiation as reflected by neurite outgrowth through a direct interaction with FGFR in primary cultures of three different neuronal cell types all expressing FGFR subtype 1: dopaminergic, hippocampal and cerebellar granule neurons. Moreover, we show that the FGL peptide promotes neuronal survival upon induction of cell death in the same three cell types. The effects of the FGL peptide are shown to depend on activation of FGFR and the MAPK and PI3K intracellular signalling pathways, all three kinases being necessary for the effects of FGL on neurite outgrowth and neuronal survival. The neural cell adhesion molecule, NCAM, is a membraneassociated glycoprotein expressed on the surface of neurons and glial cells. NCAM plays a key role in morphogenesis of the nervous system, synaptic plasticity in relation to learning and memory consolidation, and regeneration of damaged neural tissue (Rønn et al. 1998).NCAM is a member of the immunoglobulin (Ig) superfamily and mediates cell)cell adhesion. It is involved in homophilic interactions (NCAM binding to NCAM) between opposing, NCAM-expressing cells and heterophilic binding between NCAM and a series of proteins including the fibroblast growth factor receptor (FGFR), the neuronal cell adhesion molecule L1 and different types of collagens and proteoglycans Crossin and Krushel 2000;Povlsen et al. 2003;Hinsby et al. 2004). Additionally, NCAM has recently been shown to bind glial cell Abbreviations used: Ab 25-35, Amyloid-b peptide; BDNF, brainderived neurotrophic factor; CGN, cerebellar granule neurons; Erk1/2, extracellular signal-regulated kinases 1 and 2; F3, fibronectin type III module; FAK, focal adhesion kinase; FGFR, fibroblast growth factor receptor; FGLd, FG loop peptide dendrimer; FGLm, FG loop peptide monomer; GDNF, glial cell line-derived neurotrophic factor; Ig, immunoglobulin; IGF-1, insulin-like growth factor 1; MAPK, Ras-mitogen activated protein kinase; NCAM, neural cell adhesion molecule; 6-OHDA, 6-hydroxydopamine; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PLCc, phospholipase Cc.