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Abstract

Blocking inhibitory factors within CNS demyelinating lesions is regarded as a promising strategy to promote remyelination. Bone morphogenetic protein 4 (BMP4) is an inhibitory factor present in demyelinating lesions. Noggin, an endogenous antagonist to BMP, has previously been shown to increase the number of oligodendrocytes and promote remyelination in vivo. However, it remains unclear how BMP4 signaling inhibits remyelination. Here we investigated the downstream signaling pathway that mediates the inhibitory effect that BMP4 exerts upon remyelination through pharmacological and transgenic approaches. Using the cuprizone mouse model of central demyelination, we demonstrate that selectively blocking BMP4 signaling via the pharmacological inhibitor LDN-193189 significantly promotes oligodendroglial differentiation and the extent of remyelination in vivo This was accompanied by the downregulation of transcriptional targets that suppress oligodendrocyte differentiation. Further, selective deletion of BMP receptor type IA (BMPRIA) within primary mouse oligodendrocyte progenitor cells (OPCs) significantly enhanced their differentiation and subsequent myelination in vitro Together, the results of this study identify that BMP4 signals via BMPRIA within OPCs to inhibit oligodendroglial differentiation and their capacity to myelinate axons, and suggest that blocking the BMP4/BMPRIA pathway in OPCs is a promising strategy to promote CNS remyelination.

Item Type:	Article
Authors/Creators:	Govier-Cole, AE and Wood, RJ and Fletcher, JL and Gonsalvez, DG and Merlo, D and Cate, HS and Murray, SS and Xiao, J
Keywords:	oligodendrocyte, myelin, multiple sclerosis, demyelinating disease, animal model
Journal or Publication Title:	eNeuro
Publisher:	Society for Neuroscience
ISSN:	2373-2822
DOI / ID Number:	10.1523/ENEURO.0399-18.2019
Copyright Information:	Copyright © 2019 Govier-Cole et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Related URLs:	Google Scholar: Fletcher, JL
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