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The Journal of Neuroscience, March 25, 2009, 29(12):3908-3919; doi:10.1523/JNEUROSCI.5672-08.2009

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Cellular/Molecular
A Laminin-2, Dystroglycan, Utrophin Axis Is Required for Compartmentalization and Elongation of Myelin Segments

Felipe A. Court,¹ Jane E. Hewitt,² Kay Davies,³ Bruce L. Patton,⁴ Antonino Uncini,⁵ Lawrence Wrabetz,¹ and M. Laura Feltri¹

¹San Raffaele Scientific Institute, Department of Genetics and Cell Biology, 20132 Milan, Italy, ²Institute of Genetics, University of Nottingham, Nottingham NG7 2UH, United Kingdom, ³Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom, ⁴Oregon Health & Science University, Portland, Oregon 97239-3098, and ⁵University "G. d'Annunzio" and the Degenerative Diseases Unit, Aging Research Center, Centro Studi Invecchiamento, "G. d'Annunzio" University Foundation Chieti-Pescara, I-66013 Chieti, Italy

Correspondence should be addressed to either of the following: Maria Laura Feltri, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy, Email: feltri.laura{at}hsr.it; or Felipe A. Court, Department of Physiological Sciences, Universidad Católica de Chile, Avenida B. O'Higgins 340/Casilla 114-D Santiago, Chile, E-mail: Email: fcourt{at}bio.puc.cl

Animal and plant cells compartmentalize to perform morphogenetic functions. Compartmentalization of myelin-forming Schwann cells may favor elongation of myelin segments to the size required for efficient conduction of nerve impulses. Compartments in myelinated fibers were described by Ramón y Cajal and depend on periaxin, mutated in the hereditary neuropathy Charcot–Marie–Tooth disease type 4F (Charcot–Marie–Tooth 4F). Lack of periaxin in mice causes loss of compartments, formation of short myelin segments (internodes) and reduced nerve conduction velocity. How compartments are formed and maintained, and their relevance to human neuropathies is largely unknown. Here we show that formation of compartments around myelin is driven by the actin cytoskeleton, and maintained by actin and tubulin fences through linkage to the dystroglycan complex. Compartmentalization and establishment of correct internodal length requires the presence of glycosylated dystroglycan, utrophin and extracellular laminin-2/211. A neuropathic patient with reduced internodal length and nerve conduction velocity because of absence of laminin-2/211 (congenital muscular dystrophy 1A) also shows abnormal compartmentalization. These data link formation of compartments through a laminin2, dystroglycan, utrophin, actin axis to internodal length, and provide a common pathogenetic mechanism for two inherited human neuropathies. Other cell types may exploit dystroglycan complexes in similar fashions to create barriers and compartments.

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Received Nov. 27, 2008; revised Jan. 21, 2009; accepted Jan. 24, 2009.

Correspondence should be addressed to either of the following: Maria Laura Feltri, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy, Email: feltri.laura{at}hsr.it; or Felipe A. Court, Department of Physiological Sciences, Universidad Católica de Chile, Avenida B. O'Higgins 340/Casilla 114-D Santiago, Chile, E-mail: Email: fcourt{at}bio.puc.cl

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