Axonal growth mediated by cell adhesion molecules requires activation of fibroblast growth factor receptors.

During nervous system development neurons extend axons which navigate along precise pathways to innervate specific target tissues, often over long distances. The distal tip of the axon, the growth cone, plays a major role in determining the direction and distance of axonal outgrowth. A variety of outgrowth-promoting or -inhibitory soluble and matrixor cell-associated molecules encountered by the axon are recognized by receptors in the growth cone, thereby giving positional and guidance information to the neuron. The cell adhesion molecules (CAMs) NCAM, N-cadherin and L 1 are three growth-cone receptors which mediate cell-cell interactions primarily by a homophilic interaction with the same CAM expressed on the surface of other neuronal or nonneuronal cells such as muscle cells, astrocytes and Schwann cells [l]. A number of experiments in vitro have shown that neuronal cells extend neurites when cultured on monolayers of cells expressing CAMs. Using a co-culture model in which neurons are cultured on top of monolayers of 3T3 fibroblasts expressing transfected NCAM, N-cadherin or L1, we have shown that these CAMs promote neurite outgrowth by activating a specific signalling cascade in the neuron, which culminates in calcium influx through Land N-type calcium channels [Z]. Activation of the second messenger pathway independently of CAMs, by using potassium depolarization to open calcium channels, is sufficient to mimic the neurite outgrowth response [3]. This, together with the finding that a soluble chimeric form of L1 can activate the pathway and stimulate neurite outgrowth from cerebellar neurons [4], shows that intracellular signalling following CAM binding is more important for the neurite outgrowth response than adhesion. A number of recent findings together suggest that CAMs may be signalling through fibroblast growth factor (FGF) receptors (FGFRs) to promote neurite outgrowth. The activation of FGFR tyrosine kinase domains following dimerization induced by