αβ1 Integrins Are Required For Normal Peripheral Nerve Development

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Adhesion to basal lamina is required for Schwann cells (SC) to form normal myelin in peripheral nerves. In human Congenital Muscular Dystrophy (CMD), mutations in laminin 2 (α2 chain) cause a dysmyelinating peripheral neuropathy with slow nerve conduction velocities. The dy2J/dy2J mouse also carries a mutation in the laminin α2 chain, and is considered an animal model for CMD. The dysmyelination in the dy2J/dy2J mouse is dramatic in nerve roots, where SC fail to sort bundles of naked axons. In distal peripheral nerves, myelination can proceed, even if axon/SC interactions and nodes of Ranvier are abnormal. Which of the SC laminin receptors, integrins or dystroglycan mediate these functions is unclear because targeted inactivation of those genes results in embryonic death in mice prior to myelination. Several in vitro studies suggest β1 integrin as a candidate for a role in axon/SC interaction and myelination. To inactivate the β1 integrin gene (mIntb1) in SC only, we produced transgenic mice expressing Cre recombinase using the vector mP0TOT, that activates expression of genes in SC in parallel with P0 during development. By crossing mP0TOT(Cre) mice with mice carrying a mIntb1 flanked by loxP sites of recombination, we produced mice lacking β1 integrin specifically in SC. These mice have a severe dysmyelinating peripheral neuropathy, originating in embryonic nerve development. Although Schwann cells populate the length of forming nerves, and are present in numbers comparable to wildtype nerves, they are unable to penetrate bundles of naked axons in order to sort and ensheath them. In some nerve fascicles, SC can bypass the block, even in the absence of β1 integrin, and myelinate normally. These data show that αβ1 integrins are necessary for normal Schwann cell‐axon interactions, but not for myelination per se. The similarity of this phenotype to that of dy2J/dy2J mouse suggests that αβ1 integrins mediate some of the effects of altered laminin‐2 in impaired CMD peripheral nerves.