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¹ Department of Biological and Technological Research and ² Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy
³ Department of Biomedical Sciences, University of Modena and Reggio Emilia, 42100 Reggio Emilia, Italy
⁴ National Institute for Medical Research, London NW7 1AA, England, UK

Correspondence to M. Laura Feltri: feltri.laura{at}hsr.it

Myelin is a multispiraled extension of glial membrane that surrounds axons. How glia extend a surface many-fold larger than their body is poorly understood. Schwann cells are peripheral glia and insert radial cytoplasmic extensions into bundles of axons to sort, ensheath, and myelinate them. Laminins and ß1 integrins are required for axonal sorting, but the downstream signals are largely unknown. We show that Schwann cells devoid of ß1 integrin migrate to and elongate on axons but cannot extend radial lamellae of cytoplasm, similar to cells with low Rac1 activation. Accordingly, active Rac1 is decreased in ß1 integrin–null nerves, inhibiting Rac1 activity decreases radial lamellae in Schwann cells, and ablating Rac1 in Schwann cells of transgenic mice delays axonal sorting and impairs myelination. Finally, expressing active Rac1 in ß1 integrin–null nerves improves sorting. Thus, increased activation of Rac1 by ß1 integrins allows Schwann cells to switch from migration/elongation to the extension of radial membranes required for axonal sorting and myelination.

Abbreviations used in this paper: CA, constitutively active; DRG, dorsal root ganglia; E, embryonic day; MBP, myelin basic protein; P, postnatal day; PAK, p21-activated kinase; PBD, PAK binding domain; PLL, poly-L-lysine; SC, Schwann cell; wt, wild-type.

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