Stabilization of the myelin sheath: Alpha6beta4 integrin and dystroglycan cooper

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J Neurosci. 2008 Jun 25;28(26):6714-9.

Alpha6beta4 integrin and dystroglycan cooperate to stabilize the

myelin sheath.

Nodari A, Previtali SC, Dati G, Occhi S, Court FA, Colombelli C,

Zambroni D, Dina G, Del Carro U, KP, Quattrini A, Wrabetz L,

Feltri ML.

Department of Biological and Technological Research, San Raffaele

Scientific Institute, 20132 Milan, Italy.

Schwann cells integrate signals deriving from the axon and the basal

lamina to myelinate peripheral nerves. Integrin alpha6beta4 is a

laminin receptor synthesized by Schwann cells and displayed apposed

to the basal lamina. alpha6beta4 integrin expression in Schwann cells

is induced by axons at the onset of myelination, and rises in

adulthood.

The beta4 chain has a uniquely long cytoplasmic domain that interacts

with intermediate filaments such as dystonin, important in peripheral

myelination. Furthermore, alpha6beta4 integrin binds peripheral

myelin protein 22, whose alteration causes the most common

demyelinating hereditary neuropathy.

All these data suggest a role for alpha6beta4 integrin in peripheral

nerve myelination. Here we show that ablating alpha6beta4 integrin

specifically in Schwann cells of transgenic mice does not affect

peripheral nerve development, myelin formation, maturation, or

regeneration.

However, consistent with maximal expression in adult nerves,

alpha6beta4 integrin-null myelin is more prone to abnormal folding

with aging. When the laminin receptor dystroglycan is also ablated,

major folding abnormalities occur, associated with acute

demyelination in some peripheral nervous system districts.

These data indicate that, similar to its role in skin, alpha6beta4

integrin confers stability to myelin in peripheral nerves.