Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 23

Abstract

Laminin is required for normal peripheral nerve development, as mutations causing absence of laminin‐2 cause hereditary peripheral neuropathies (neuropathy of Merosin‐Deficient Congenital Muscular Dystrophy and dystrophic mouse). We study the laminin receptors, integrins and dystroglycan, that link laminin in the basal lamina to the Schwann cells cytoskeleton. This linkage is defective in an animal model of Charcot‐Marie‐Tooth 4F, in which the Periaxin/Dystrogycan/DRP‐2 complex is disrupted. To study the role of laminin receptors in these peripheral neuropathies, we inactivated the gene for beta1 integrin and dystroglycan specifically in Schwann cells of transgenic mice. alpha6beta1 integrin is present in Schwann cells and their precursors before myelination, the absence of beta1 integrin causes a severe peripheral neuropathy due to the failure of Schwann cells to interact with axons during axonal sorting. Although more severe, this neuropathy is morphologically similar to that of dystrophic mice. In contrast, dystroglycan first appears in Schwann cells after axonal sorting and just prior to myelination (pro‐myelinating Schwann cells). In the absence of dystroglycan, mice develop a neuropathy with abnormally folded myelin sheaths, slow conduction velocity and loss of DRP‐2, similar to that of periaxin‐null mice. These data show that alpha6beta1 integrin and dystroglycan subserve different roles during nerve development, and that they are involved at different steps in the pathogenesis of Merosin‐Deficient Congenital Muscular Dystrophy and Charcot‐Marie‐Tooth 4F.