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

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.

The Vav GEF Family: An Evolutionary and Functional Perspective

“…When Vav3 is absent, this GABAergic wiring is not properly established, leading to the loss of the tonic inhibition exerted by the ventral over the rostral area of the ventrolateral medulla, and the development of multiple sympathetic-dependent physiological defects in mice [111,114,125,126]. Further functions of Vav3 inside the nervous system include the blockage of the differentiation of oligodendrocyte precursors and the promotion of myelination processes during both development and injury recovery [127]. Outside the central nervous system, Vav3 has been linked to the regulation of the differentiation of progenitor cells during the development of the mouse retina, the permeability of endothelial cells, the maturation of osteoclasts, and the regulation of antifungal innate immunity [95,128,129,130].…”

Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system

“…Yet a subsequent literature search suggested that Vav3, Vcam1, and Cdc14a were the most likely genes influencing NADP + concentrations. Vav3 (Chr3:109340653–109685698 bp; 48.13 cM; GRCm38) is a Rho GTPase regulating guanine nucleotide exchange factor (GEF) [ 91 ]. The Vav protein family, including Vav3, are key activators of the Card9/NF-κB pathway in immunity [ 92 ].…”

Deletion of the Nucleotide Exchange Factor Vav3 Enhances Axonal Complexity and Synapse Formation but Tampers Activity of Hippocampal Neuronal Networks In Vitro

“…Several studies have shown that Vav proteins are potential activators of Rho GTPase family members [7,8]. It has been reported that Vav3 strongly unfolds its nucleotide exchange activity with the targets RhoA and RhoG, whereas Rac1 is activated less efficiently, and Cdc42 not at all [6,8,38]. Interestingly, Vav3 has been found enriched in hippocampal synapses [39] and in hippocampal neuron axons after 5 days in vitro [22].…”