CMT 4F: A laminin-2, dystroglycan, utrophin axis is required for compartmentaliz

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J Neurosci. 2009 Mar 25;29(12):3908-19.

A laminin-2, dystroglycan, utrophin axis is required for compartmentalization

and elongation of myelin segments.

Court FA, Hewitt JE, Davies K, Patton BL, Uncini A, Wrabetz L, Feltri ML.

San Raffaele Scientific Institute, Department of Genetics and Cell Biology,

20132 Milan, Italy.

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.