Conditional Deletion of the Itgb4 Integrin Gene in Schwann Cells Leads to Delayed Peripheral Nerve Regeneration

Several different integrins participate in the complex interactions that promote repair of the peripheral nervous system. The role of the integrin alpha 6 beta 4 in peripheral nerve regeneration was investigated in mice by cre-mediated deletion of the Itgb4 (beta 4) gene in Schwann cells. After a crush lesion of the sciatic nerve, the recovery of motor, but not that of sensory, nerve function in beta 4(-/-) mice was delayed. Immunostaining of neurofilament-200 showed that there also is a significant reduction in the number of newly outgrowing nerve sprouts in beta 4(-/-) mice. Morphometric quantitative measurements revealed that fewer axons are myelinated in the nonlesioned beta 4(-/-) nerves. After a sciatic nerve crush lesion, beta 4(-/-) mice did not only have fewer myelinated axons compared with lesioned wild-type nerve, but their axons also showed a higher g-ratio and a thinner myelin sheath, pointing at reduced myelination. This study revealed that the beta 4 protein remains expressed in the early stages of peripheral regeneration, albeit at levels lower than those before the lesion was inflicted, and showed that laminin deposition is not altered in the absence of beta 4. These results together demonstrate that integrin alpha 6 beta 4 plays an essential role in axonal regeneration and subsequent myelination.