Alpha4 integrin is expressed during peripheral nerve regeneration and enhances neurite outgrowth.
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 alpha4 integrins. Here we show that alpha4 integrins are expressed on dorsal root ganglion neuron cell bodies and growth cones in the sciatic 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 extends neurites poorly on fibronectin, does so efficiently when alpha4 is expressed in the cells. Experiments using chimeric integrins expressed in PC12 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 intracellular adapter protein paxillin. These experiments suggest an important role for alpha4 integrin and paxillin in peripheral nerve regeneration and show how alternative splicing of fibronectin may provide a mechanism to enhance repair after injury.
Vogelezang
M G
MG
Department of Medical Genetics, University of Cambridge and Cambridge Centre for Brain Repair, University Forvie Site, Cambridge, CB2 2PY, United Kingdom.
Liu
Z
Z
Relvas
J B
JB
Raivich
G
G
Scherer
S S
SS
ffrench-Constant
C
C
D017398:Alternative Splicing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D039441:Integrin alpha4; D051379:Mice; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051419:Paxillin; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012584:Sciatic Nerve / Q000293:injuries / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D015703:Antigens, CD; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D051419:Paxillin; D010446:Peptide Fragments; D010750:Phosphoproteins; C496062:Pxn protein, mouse; C496063:Pxn protein, rat; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D039441:Integrin alpha4