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

Ulc, Annika, Zeug, Andre, Bauch, Juliane, van Leeuwen, Simon, Kuhlmann, Tanja, ffrench-Constant, Charles ORCID:, Ponimaskin, Evgeni and Faissner, Andreas (2018) The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions. Glia, 67 (2). pp. 376-392. ISSN 0894-1491

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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.

Item Type: Article
Additional Information: Funding Information: information German Research Foundation (DFG), Grant/Award Number: FA 159/24-1; REBIRTH (EXC 62/3); SFB 642 TPA24; SPP 1757 FA 159/20-1,2; ZE 994/2; Ruhr-Universität Bochum, Grant/Award Number: President's Special Program Call 2008; Stem Cell Network NRWWe acknowledge Sabine Kindermann, Marion Voelzkow, Sandra Lata, Holger Schlierenkamp, Tanja Rollnik, and Sabine Adler for excellent technical support and Jun.-Prof. Dr. Olivia Masseck and M.Sc. Martin Kubitschke for advice with the use of the Leica TCS SP8 confocal microscope. We also thank Dr. Lars Roll, Dr. Marie E. Bechler, Dr. Veronique E. Miron, Dr. Andrew Jarjour and Dr. Marie Harrisingh for their help and discussions. We gratefully acknowledge grant support by the Stem Cell Network North Rhine-Westphalia, the German Research Foundation (DFG: SFB 642 TPA24; SPP-1757, Fa 159/20-1,2; Fa 159/24-1) to AF; the Cluster of Excellence REBIRTH (EXC 62/3) to EP. AZ obtained support from the German Research Foundation (ZE 994/2) and the REBIRTH Excellence Cluster. We would like to thank Prof. Matsuda for the kind gift of RaichuEV-RhoA, RaichuEV-Cdc42 and RaichuEV-Rac1 plasmids.
Uncontrolled Keywords: cuprizone model of demyelination,fret,guanine nucleotide exchange factor,myelin,neuron-glia interaction,oligodendrocyte,regeneration of myelin,neurology,cellular and molecular neuroscience ,/dk/atira/pure/subjectarea/asjc/2800/2808
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jul 2022 14:31
Last Modified: 23 Oct 2022 03:56
DOI: 10.1002/glia.23548

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