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.
Subject(s)
Bone Morphogenetic Protein 4/metabolism , Bone Morphogenetic Protein Receptors, Type I/metabolism , Demyelinating Diseases/metabolism , Neural Stem Cells/metabolism , Oligodendroglia/metabolism , Remyelination , Signal Transduction , Animals , Bone Morphogenetic Protein 4/antagonists & inhibitors , Bone Morphogenetic Protein Receptors, Type I/deficiency , Cell Differentiation/drug effects , Demyelinating Diseases/drug therapy , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Stem Cells/drug effects , Oligodendroglia/drug effects , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Remyelination/drug effectsABSTRACT
Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro. Gas6 can bind to and activate all three TAM receptors, but the high level of expression of Tyro3 on oligodendrocytes makes this receptor the principal candidate for transducing the pro-myelinating effect of Gas6. In this study, we establish that in the absence of Tyro3, the pro-myelinating effect of Gas6 is lost, that developmental myelination is delayed and that the myelin produced is thinner than normal. We show that this effect is specific to the myelination process and not due to changes in the proliferation or differentiation of oligodendrocyte precursor cells. We have further demonstrated that the reduction in myelination is due to the loss of Tyro3 on oligodendrocytes, and this effect may be mediated by activation of Erk1. Collectively, our findings indicate the critical importance of Tyro3 in potentiating central nervous system myelination. GLIA 2017 GLIA 2017;65:581-591.
Subject(s)
Central Nervous System/metabolism , Myelin Sheath/metabolism , Oligodendroglia/physiology , Organogenesis/physiology , Receptor Protein-Tyrosine Kinases/metabolism , Age Factors , Animals , Animals, Newborn , Cell Lineage , Cells, Cultured , Central Nervous System/cytology , Gene Expression Regulation, Developmental/genetics , In Vitro Techniques , Intercellular Signaling Peptides and Proteins/deficiency , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred C57BL , Myelin Basic Protein/metabolism , Myelin Sheath/genetics , Myelin Sheath/ultrastructure , Optic Nerve/cytology , Organogenesis/genetics , Proto-Oncogene Proteins/metabolism , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/geneticsABSTRACT
Substantial progress has been made in identifying the extracellular signalling pathways that regulate neural stem and precursor cell biology in the central nervous system (CNS). The bone morphogenetic proteins (BMPs), in particular BMP4, are key players regulating neuronal and glial cell development from neural precursor cells in the embryonic, postnatal, and injured CNS. Here we review recent studies on BMP4 signalling in the generation of neurons, astrocytes, and oligodendroglial cells in the CNS. We also discuss putative mechanisms that BMP4 may utilise to influence glial cell development following CNS injury and highlight some questions for further research.
