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The Journal of Neuroscience, October 12, 2005, 25(41):9418-9427; doi:10.1523/JNEUROSCI.2068-05.2005

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Development/Plasticity/Repair
Both Laminin and Schwann Cell Dystroglycan Are Necessary for Proper Clustering of Sodium Channels at Nodes of Ranvier

Simona Occhi,¹ Desirée Zambroni,¹ Ubaldo Del Carro,² Stefano Amadio,² Erich E. Sirkowski,³ Steven S. Scherer,³ Kevin P. Campbell,⁴ Steven A. Moore,⁵ Zulin-L. Chen,⁶ Sidney Strickland,⁶ Antonio Di Muzio,⁷ Antonino Uncini,⁷ Lawrence Wrabetz,¹ and M. Laura Feltri¹

¹Dibit and ²Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy, ³Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6077, ⁴Howard Hughes Medical Institute and ⁵Department of Pathology, University of Iowa, Iowa City, Iowa 52242, ⁶Laboratory of Neurobiology and Genetics, Department of Neurology, The Rockefeller University, New York, New York 10021, and ⁷Department of Oncology and Neurosciences, University "G. d'Annunzio," and Degenerative Diseases Unit, Aging Research Center, Centro Studi Invecchiamento, "G. d'Annunzio" University Foundation, I-66013 Chieti-Pescara, Italy

Nodes of Ranvier are specialized axonal domains, at which voltage-gated sodium channels cluster. How axons cluster molecules in discrete domains is mostly unknown. Both axons and glia probably provide constraining mechanisms that contribute to domain formation. Proper sodium channel clustering in peripheral nerves depends on contact from Schwann cell microvilli, where at least one molecule, gliomedin, binds the sodium channel complex and induces its clustering. Furthermore, mice lacking Schwann cell dystroglycan have aberrant microvilli and poorly clustered sodium channels. Dystroglycan could interact at the basal lamina or at the axonglial surface. Because dystroglycan is a laminin receptor, and laminin 2 mutations [merosin-deficient congenital muscular dystrophy (MDC1A)] cause reduced nerve conduction velocity, we asked whether laminins are involved. Here, we show that the composition of both laminins and the dystroglycan complex at nodes differs from that of internodes. Mice defective in laminin 2 have poorly formed microvilli and abnormal sodium clusters. These abnormalities are similar, albeit less severe, than those of mice lacking dystroglycan. However, mice lacking all Schwann cell laminins show severe nodal abnormalities, suggesting that other laminins compensate for the lack of laminin 2. Thus, although laminins are located at a distance from the axoglial junction, they are required for proper clustering of sodium channels. Laminins, through their specific nodal receptors and cytoskeletal linkages, may participate in the formation of mechanisms that constrain clusters at nodes. Finally, abnormal sodium channel clusters are present in a patient with MDC1A, providing a molecular basis for the reduced nerve conduction velocity in this disorder.

Key words: laminin; Schwann cell; node of Ranvier; microvilli; dystrophic; sodium channels

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Received Feb 10, 2005; revised August 30, 2005; accepted August 31, 2005.

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