Chapter Six - Bone Morphogenetic Proteins: Inhibitors of Myelination in Development and Disease
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).
References (110)
- et al.
Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain
Molecular and Cellular Neurosciences
(2001) - et al.
The bone morphogenetic protein antagonist noggin protects white matter after perinatal hypoxia-ischemia
Neurobiology of Disease
(2011) - et al.
Consequences of noggin expression by neural stem, glial, and neuronal precursor cells engrafted into the injured spinal cord
Experimental Neurology
(2005) - et al.
Wnt signaling is sufficient to perturb oligodendrocyte maturation
Molecular and Cellular Neuroscience
(2009) - et al.
Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment
Developmental Biology
(2003) - et al.
Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells
Neuron
(1996) Bioenergetics of cerebral ischemia: A cellular perspective
Neuropharmacology
(2008)- et al.
Astrocytes promote myelination in response to electrical impulses
Neuron
(2006) - et al.
Human oligodendrocytes derived from embryonic stem cells: Effect of noggin on phenotypic differentiation in vitro and on myelination in vivo
Molecular and Cellular Neurosciences
(2007) - et al.
Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis
Journal of Neuroimmunology
(2005)
The near-term (late preterm) human brain and risk for periventricular leukomalacia: A review
Seminars in Perinatology
A role for Noggin in the development of oligodendrocyte precursor cells
Developmental Biology
Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm
Cell
Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection
Cell
Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mamalian central nervous system
Neuron
Expression of bone morphogenetic protein 6 and transforming growth factor b1 in the rat brain after a mild and reversible ischemic damage
Brain Research
Action range of BMP is defined by its N-terminal basic amino acid core
Current Biology
Determination of neuroepithelial cell fate: Induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog
Developmental Biology
BMP signaling mutant mice exhibit glial cell maturation defects
Molecular and Cellular Neurosciences
Oligodendrocyte maturation is inhibited by bone morphogenetic protein
Molecular and Cellular Neurosciences
Treatment of spinal cord injury by transplantation of fetal neural precursors cells engineered to express BMP inhibitor
Experimental Neurology
Traumatic injury-induced BMP 7 expression in the adult rat spinal cord
Brain Research
Glial cell migration directed by axon guidance cues
Trends in Neurosciences
Dorsal spinal cord inhibits oligodendrocyte development
Developmental Biology
A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development
Neuron
A functional role for EGFR signaling in myelination and remyelination
Nature Neuroscience
BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb
Development
Activation of kainate receptors sensitizes oligodendrocytes to complement attack
Journal of Neuroscience: The Official Journal of the Society for Neuroscience
Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitis
Journal of Neuroscience Research
Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia
The Journal of Neuroscience
Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury
The Journal of Neuroscience
Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation
Nature Medicine
Astrogliosis in EAE spinal cord: Derivation from radial glia, and relationships to oligodendroglia
Glia
Fibroblast growth factors and their receptors in oligodendrocyte development: Implications for demyelination and remyelination
Developmental Neuroscience
Proligodendroblast antigen (POA), a developmental antigen expressed by A007/O4-positive oligodendrocyte progenitors prior to the appearance of sulfatide and galactocerebroside
Journal of Neurochemistry
A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development
Development
Induction of Olig2 precursors by FGF involves BMP signalling blockade at the Smad level
PLoS One
Loss of p27Kip1 function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation
Development
Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination
Journal of Neurochemistry
FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway
Development
Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury
The European Journal of Neuroscience
Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells
Stem Cells
Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells
The Journal of Neuroscience
Relationship of iron to oligodendrocytes and myelination
Glia
Detection of two transforming-growth-factor-beta-related morphogens, bone morphogenetic proteins-4 and − 5, in RNA of multiple sclerosis and Creutzfeld-Jakob disease lesion
Acta Neuropathologica
Bone morphogenetic protein inhibition promotes neurological recovery after intraventricular hemorrhage
The Journal of Neuroscience
Regulation of oligodendrocyte differentiation and myelination
Science
Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS
Genes and Development
Canonical Wnt signaling requires the BMP pathway to inhibit oligodendrocyte maturation
ASN Neuro
Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions
Annals of Neurology
Cited by (31)
Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models
2021, Neurobiology of DiseaseCitation Excerpt :Blocking RGMa interaction with BMPs and thus inhibiting BMP signalling could be one of the important mechanisms for RGMa antagonists in mediating neuroregeneration and remyelination. As demonstrated in a BMP competition ELISA (Fig. 2A), elezanumab was able to block RGMa binding to BMP-2 and BMP-4 which are known inhibitors of myelination in development and disease (Grinspan, 2015; Grinspan, 2020). In order to test the functional activity of anti-N-RGMa mAbs in inhibiting RGMa mediated BMP signalling, we established a dual-transfected stable HEK293 cell line overexpressing membrane hRGMa and a BMP responsive element (BRE)-Luc reporter gene as depicted in Fig. 2B. Elezanumab potently inhibited RGMa mediated BMP signalling via the SMAD1/5/8 pathway, with an IC50 around 97 ± 19 pM, which is comparable to those of its parental mAbs AE12-1 (IC50 = 93 ± 21 pM) and AE12-1Y (IC50 = 91 ± 9 pM) (Table 1).
Endothelial Nitric Oxide Synthase–Deficient Mice: A Model of Spontaneous Cerebral Small-Vessel Disease
2021, American Journal of PathologyIntrinsic and extrinsic regulators of oligodendrocyte progenitor proliferation and differentiation
2021, Seminars in Cell and Developmental BiologyBMP9 expression in the adult rat brain
2021, Journal of Chemical NeuroanatomyCitation Excerpt :In addition, BMPs are also known to inhibit myelination and remyelination in the adult CNS (Wang et al., 2020; Eixarch et al., 2020). For example, BMPs inhibit myelin protein expressions in immature oligodendrocytes (Grinspan, 2015). In addition, inhibition of the BMP signaling pathway ameliorated clinical symptoms of experimental autoimmune encephalomyelitis (Eixarch et al., 2020).
White matter injury and neurodevelopmental disabilities: A cross-disease (dis)connection
2020, Progress in Neurobiology