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The Journal of Neuroscience, September 1, 2001, 21(17):6732-6744

alpha 4 Integrin Is Expressed during Peripheral Nerve Regeneration and Enhances Neurite Outgrowth

Mariette G. Vogelezang1, ZhiQiang Liu2, João B. Relvas1, Gennadij Raivich2, Steven S. Scherer3, and Charles ffrench-Constant1

1 Department of Medical Genetics, University of Cambridge and Cambridge Centre for Brain Repair, University Forvie Site, Cambridge, CB2 2PY, United Kingdom, 2 Department of Neuromorphology, Max Planck Institute for Neurobiology, D-82152 Martinsried, Germany, and 3 Department of Neurology, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

We have shown previously that repair in the peripheral nervous system is associated with a reversion to an embryonic pattern of alternative splicing of the extracellular matrix molecule fibronectin. One of the consequent changes is a relative increase in the number of fibronectins expressing the binding site for alpha 4 integrins. Here we show that alpha 4 integrins are expressed on dorsal root ganglion neuron cell bodies and growth cones in the sciatic nerve during regeneration and that the interaction of alpha 4 integrin with alternatively spliced isoforms of recombinant fibronectins containing the alpha 4 binding site enhances neurite outgrowth in dorsal root ganglion neurons. The pheochromocytoma (PC12) neuronal cell line, which normally extends neurites poorly on fibronectin, does so efficiently when alpha 4 is expressed in the cells. Experiments using chimeric integrins expressed in PC12 cells show that the alpha 4 cytoplasmic domain is necessary and sufficient for this enhanced neurite outgrowth. In both dorsal root ganglion neurons and PC12 cells the alpha 4 cytoplasmic domain is tightly linked to the intracellular adapter protein paxillin. These experiments suggest an important role for alpha 4 integrin and paxillin in peripheral nerve regeneration and show how alternative splicing of fibronectin may provide a mechanism to enhance repair after injury.

Key words: integrin; peripheral nerve regeneration; fibronectin; alternative splicing; paxillin; alpha 4; PC12 cell; dorsal root ganglia; chimera; LDV

Copyright © 2001 Society for Neuroscience  0270-6474/01/21176732-13$05.00/0




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