alpha 4 Integrin is expressed during peripheral nerve regeneration and enhances neurite outgrowth

We have shown previously that repair in the peripheral nervous system is as sociated with a reversion to an embryonic pattern of alternative splicing o f the extracellular matrix molecule fibronectin. One of the consequent chan ges is a relative increase in the number of fibronectins expressing the bin ding site for alpha4 integrins. Here we show that alpha4 integrins are expr essed on dorsal root ganglion neuron cell bodies and growth cones in the sc iatic nerve during regeneration and that the interaction of alpha4 integrin with alternatively spliced isoforms of recombinant fibronectins containing the alpha4 binding site enhances neurite outgrowth in dorsal root ganglion neurons. The pheochromocytoma (PC12) neuronal cell line, which normally ex tends neurites poorly on fibronectin, does so efficiently when alpha4 is ex pressed in the cells. Experiments using chimeric integrins expressed in PC1 2 cells show that the alpha4 cytoplasmic domain is necessary and sufficient for this enhanced neurite outgrowth. In both dorsal root ganglion neurons and PC12 cells the alpha4 cytoplasmic domain is tightly linked to the intra cellular adapter protein paxillin. These experiments suggest an important r ole for alpha4 integrin and paxillin in peripheral nerve regeneration and s how how alternative splicing of fibronectin may provide a mechanism to enha nce repair after injury.