Elsevier

Vitamins & Hormones

Volume 99, 2015, Pages 195-222
Vitamins & Hormones

Chapter Six - Bone Morphogenetic Proteins: Inhibitors of Myelination in Development and Disease

https://doi.org/10.1016/bs.vh.2015.05.005Get rights and content

Abstract

Myelin, the lipid membrane that surrounds axons, is critical for the propagation of nervous impulses and axonal maintenance. The destruction of myelin or lack of myelin formation due to disease or injury causes severe motor and cognitive disability. Regeneration of myelin is theoretically possible but rarely happens. Myelin is synthesized as the plasma membrane of the oligodendrocyte in the central nervous system. During development, myelin and oligodendrocytes are generated from oligodendrocyte progenitors through a process modulated by extrinsic growth factors signaling to cell-intrinsic proteins. Among the key extrinsic factors are the bone morphogenetic proteins (BMPs), potent inhibitors of oligodendrocyte differentiation and myelin protein expression, likely serving to regulate myelination temporally and spatially. BMPs also promote astrocyte generation. Given the inhibitory role of BMP in oligodendrogliogenesis during development, the expression of BMP during demyelinating disease or injury was investigated, as was whether BMP upregulation could serve to prevent regeneration by both direct inhibition of myelination and increases in astrogliosis. BMPs, predominantly BMP4, were increased in animal models of spinal cord injury, stroke, multiple sclerosis, and perinatal white matter injury. A number of studies inhibited BMP signaling by infusing the injury site with the BMP-specific inhibitor noggin or transplanting stem cells engineered to secrete noggin. In most cases, noggin increased the numbers of mature oligodendrocytes and decreased numbers of astrocytes. Some studies also showed functional improvement. BMP is one of several inhibitory growth factors that now appear to inhibit myelin regeneration. Common downstream mechanisms among these factors are likely to be identified.

Introduction

Bone morphogenetic proteins (BMPs), although first identified for their important roles in bone formation, have been recognized as key regulators of development in many organ systems of the body, especially the central nervous system. BMPs modulate the development of neural stem cells capable of becoming both neurons and glia. Oligodendrocytes, glial cells that synthesize the myelin as part of their plasma membrane, are particularly sensitive to BMP regulation during embryonic development. In this chapter, we demonstrate that BMPs are also powerful inhibitors of remyelination following demyelinating disease and injury. However, to appreciate the significance of the role of BMP in myelination and remyelination, one needs to first understand the importance of myelination to the nervous system.

Section snippets

Myelin Is Required for Salutatory Conduction of Nervous Impulses and Axonal Maintenance

Myelin, the lipid-rich membrane that surrounds axons, ensures conduction of nervous impulses in a salutatory manner and also maintains axonal integrity. Lack of myelin results in physical deficits, cognitive and behavioral deficits and can be life-threatening. Spontaneous regeneration of myelin following a pathological event can occur but usually only from a single acute event (Lasiene, Shupe, Perlmutter, & Horner, 2008). Most diseases of myelin are more chronic in nature. The most prevalent

Oligodendrocytes Develop from Progenitors Through an Orderly Process Controlled by Extrinsic and Intrinsic Signaling Factors

OPCs progress to mature myelinating oligodendrocytes through an orderly process involving specification, proliferation, migration, and differentiation. Several stages of the oligodendrocyte lineage have been well described and characterized. OPCs, expressing the antigen identified by the A2B5 antibody as well as PDGF receptor alpha and the proteoglycan NG2 (Nishiyama et al., 1996, Ranscht et al., 1982), give rise to pro-oligodendrocytes that express the POA antigen identified by the O4

BMPs in Nervous System Development

BMPs are a family of secreted signaling factors in the transforming growth factor beta family that were identified first for their role in bone formation. They direct functions as diverse as proliferation, apoptosis, maturation, and migration. There are 20 structurally distinct forms of BMP but the number that appears to be involved in oligodendrocyte function and myelination is small. Although BMP2, 4, and 7 have been noted to have effects on glia, most studies in the glial field confine

BMPs inhibit Oligodendrogliogenesis During Development: Evidence In Vitro and In Vivo

The potential of BMPs to affect the development of oligodendrocytes and myelin was identified by two lines of inquiry. In the first, addition of soluble BMP to cultures of rodent neurospheres directed the development of neural stem cells to astrocytes over oligodendrocytes or neurons (Gross et al., 1996). Later experiments using cultures of rodent OPCs or preprogenitors, an even earlier stage of the lineage of the oligodendrocyte lineage, showed that treatment with BMP2 or 4 inhibited the

Endogenous Role of BMPs in Development

Studies of the endogenous role of BMPs in the generation of oligodendrocytes and myelin have produced conflicting results. These studies are based on conditional genetic deletions of BMP receptors. Because BMPs are involved in so many fundamental aspects of development, global genetic deletions of specific BMP ligands or their receptors result in embryonic lethality. Additionally, conditional deletions of BMP ligands would need to target multiple BMPs to avoid compensation. BMP signals through

Downstream of BMPs: Putative Mechanism of BMP Action

The mechanism by which OPCs mature and the controls on this mechanism are complex and still incompletely understood. As OPCs begin to mature, proliferation is halted through downregulation of factors such as P27kip1, CDK2, and p53. Inhibition of proliferation is necessary but not sufficient to induce differentiation (Casaccia-Bonnefil et al., 1999, Tang et al., 1999). A number of transcription factors are required for differentiation, including Olig 1 and 2, Sox 10, Nkx2.2, Sox 17 (for review,

Expression of BMPs Is Increased in Demyelination Pathologies

The identification of BMPs as inhibitors of oligodendrogliogenesis during development suggested potential roles in demyelination/remyelination. Initially, a variety of models of neuropathologies were examined to determine the levels of BMP signaling, which BMPs and which cells are making the BMP on both the message and protein level. These pathologies fall into three categories: traumatic spinal cord injury, hypoxia/ischemia in adult or newborn, and demyelinating injury caused by chemical

Evidence that BMPs Restrict Remyelination

The identification of a marked increase in BMP signaling in demyelinating disease and injury plus the function of BMP to block oligodendrocyte differentiation during development suggests that it may serve to inhibit remyelination in these varied pathologies but does not prove it. For this, a number of studies have attempted to block BMP signaling to improve remyelination (Table 1). One of the challenges of this area of study is dissecting whether BMPs are inhibiting remyelination directly or by

BMPs Interact with Other Inhibitors of Myelination and Remyelination

From the perspective of the oligodendrocyte biologist, BMP4 is a potent inhibitor of myelination and remyelination and seems to be a prime candidate for intervention to promote regeneration. However, several other external signaling factors have been identified, which also inhibit myelination during development and are upregulated following demyelination. These include Wnt, FGF2, notch, LINGO, and GPR17. The Wnts are also a dorsally derived signaling factors that are often associated with BMPs.

Conclusions and Future Directions

The study of the role of BMPs in oligodendrocyte development and myelination has demonstrated that this family of signaling factors are powerful inhibitors of oligodendrogliogenesis and myelination in development and in disease. The role of BMPs in oligodendrocyte development was identified first leading to speculation that BMPs might be involved in pathologies, which has now been verified. Oligodendrocyte biologists have long claimed that the study of oligodendroglial development could

Acknowledgments

This work is supported by National MS Society RG4558A8/2 (J.B.G.), RO1 MH098742, and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children's Hospital of Philadelphia (HD26979).

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