Abstract
Blocking inhibitory factors within central nervous system (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 BMPRIA receptors within primary mouse OPCs significantly enhanced their differentiation and subsequent myelination in vitro. Together, 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 BMP4/BMPRIA pathway in OPCs is a promising strategy to promote CNS remyelination.
Significance Statement Blocking inhibitory factors within central demyelinating lesions is a promising strategy to promote remyelination. Previous studies have established that exogenous BMPs inhibit oligodendrocyte differentiation during CNS development and after injury. Here, we demonstrate that blocking endogenous BMP4 signaling via a selective pharmacological approach promotes oligodendroglial differentiation and the rate of remyelination after a central demyelinating insult in vivo. Using in vitro analysis, we identify that OPC-expressed BMPRIA receptors mediate this effect. Together, our data propose that blocking the BMP4 signaling pathway and/or BMPRIA receptors in OPCs is a promising strategy to promote CNS remyelination.
Footnotes
Authors report no conflicts of interest, or competing financial interests.
A.E.G-C. gratefully acknowledges the support provided by Australian National Health & Medical Research Council (NH&MRC) Research Training Program scholarship. This work has been supported by a Multiple Sclerosis Research Australia Research Project Grant (#14-060 to H.S.C.) and NH&MRC Project Grants (#APP1058647 to J.X., APP1105108 to S.S.M., APP1020735 to H.S.C.).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Jump to comment: