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. 2019 Feb;67(2):376-392.
doi: 10.1002/glia.23548. Epub 2018 Nov 18.

The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions

Annika Ulc  1 , Andre Zeug  2 , Juliane Bauch  1 , Simon van Leeuwen  1 , Tanja Kuhlmann  3 , Charles Ffrench-Constant  4 , Evgeni Ponimaskin  2 , Andreas Faissner  1
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The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions

Annika Ulc et al. Glia. 2019 Feb.

Abstract

The tightly controlled processes of myelination and remyelination require the participation of the cytoskeleton. The reorganization of the cytoskeleton is controlled by small GTPases of the RhoA family. Here, we report that Vav3, a Rho GTPase regulating guanine nucleotide exchange factor (GEF) is involved in oligodendrocyte maturation, myelination and remyelination. When Vav3 was eliminated by genetic recombination, oligodendrocyte precursor cell (OPC) differentiation toward mature oligodendrocytes was accelerated. In contrast, Vav3-deficient oligodendrocytes displayed a reduced capacity to myelinate synthetic microfibers in vitro. Furthermore, remyelination was impaired in Vav3 knockout cerebellar slice cultures that were demyelinated by the addition of lysolecithin. In agreement with these observations, remyelination was compromised when the cuprizone model of myelin lesion was performed in Vav3-deficient mice. When Vav3-deficient oligodendrocytes were examined with Förster resonance energy transfer (FRET)-based biosensors, an altered activation profile of RhoA GTPases was revealed on the cellular level, which could be responsible for an impaired remyelination. Taken together, this study highlights Vav3 as a novel regulator of oligodendrocyte maturation and remyelination, suggesting that manipulation of the Vav3-dependent signaling pathway could help to improve myelin repair.

Keywords: Cuprizone model of demyelination; FRET; guanine nucleotide exchange factor; myelin; neuron-glia interaction; oligodendrocyte; regeneration of myelin.

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