Inhibiting Bone Morphogenetic Protein 4 Type I Receptor Signaling Promotes Remyelination by Potentiating Oligodendrocyte Differentiation

Overview

Journal eNeuro

Specialty Neurology

Date 2019 Apr 28

PMID 31028086

Citations 6

Authors

Alistair E Govier-Cole

Rhiannon J Wood

Jessica L Fletcher

David G Gonsalvez

Daniel Merlo

Holly S Cate

Simon S Murray

Junhua Xiao

Affiliations

Soon will be listed here.

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 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 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 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.

Citing Articles

Reflective imaging of myelin integrity in the human and mouse central nervous systems.

Craig G, Ryan L, Thapar J, McNamara N, Hoffmann A, Page D Front Cell Neurosci. 2024; 18:1408182.

PMID: 39049821 PMC: 11266064. DOI: 10.3389/fncel.2024.1408182.

Remyelination in Multiple Sclerosis: Findings in the Cuprizone Model.

Leo H, Kipp M Int J Mol Sci. 2022; 23(24).

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Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination.

Saraswat D, Shayya H, Polanco J, Tripathi A, Welliver R, Pol S Nat Commun. 2021; 12(1):1923.

PMID: 33772011 PMC: 7998003. DOI: 10.1038/s41467-021-22263-4.

Inhibitors of Myelination and Remyelination, Bone Morphogenetic Proteins, are Upregulated in Human Neurological Disease.

Grinspan J Neurochem Res. 2020; 45(3):656-662.

PMID: 32030597 PMC: 7141772. DOI: 10.1007/s11064-020-02980-w.

Imaging and Quantification of Myelin Integrity After Injury With Spectral Confocal Reflectance Microscopy.

Gonsalvez D, Yoo S, Fletcher J, Wood R, Craig G, Murray S Front Mol Neurosci. 2019; 12:275.

PMID: 31803018 PMC: 6877500. DOI: 10.3389/fnmol.2019.00275.

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