147220 - inhibiting bone morphogenetic protein.pdf (6.94 MB)
Inhibiting bone morphogenetic protein 4 Type I receptor signaling promotes remyelination by potentiating oligodendrocyte differentiation
journal contribution
posted on 2023-05-21, 03:18 authored by Govier-Cole, AE, Wood, RJ, Jessica FletcherJessica Fletcher, Gonsalvez, DG, Merlo, D, Cate, HS, Murray, SS, Xiao, JBlocking 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.
History
Publication title
eNeuroVolume
6Pagination
1-22ISSN
2373-2822Department/School
Menzies Institute for Medical ResearchPublisher
Society for NeurosciencePlace of publication
United StatesRights statement
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.Repository Status
- Open