Wnt Signaling in Remyelination in Multiple Sclerosis: Friend or Foe?

Xie, Chong; Li, Zezhi; Zhang, Guang‐Xian; Guan, Yangtai

doi:10.1007/s12035-013-8584-6

Cited by 44 publications

(27 citation statements)

References 68 publications

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“…The canonical Wnt pathway is activated when extracellular Wnt binds to Frizzled membrane receptors, resulting in the stabilization of intracellular β-catenin, which enters the nucleus to promote Wnt gene transcription (Xie et al, 2014). Shimizu et al (2005) showed that OPC differentiation in the spinal cord is inhibited by Wnt signaling through the canonical β-catenin pathway (Shimizu et al, 2005).…”

Section: Restoring Function: Mediators Of Oligodendrocyte Regeneramentioning

confidence: 99%

“…Daam2 may be a potential upstream target of Wnt as its activation inhibits OPC differentiation in development and white matter injury (WMI) (Lee et al, 2015). Although there is a general consensus that canonical Wnt signaling inhibits OPC differentiation, conflicting findings have been reported (Xie et al, 2014). Wnt/β-catenin signaling pathway is essential for myelin protein expression and myelin sheath compaction in zebrafish (Tawk et al, 2011).…”

Section: Restoring Function: Mediators Of Oligodendrocyte Regeneramentioning

confidence: 99%

“…In addition, decreased MBP and PLP are found in mice lacking T-cell factor 4 (Fu et al, 2009), a transcription factor downstream of β-catenin that is expressed by OPCs during development and remyelination (Fancy et al, 2009). These studies suggest that Wnt/β-catenin signaling serves distinct functions in oligodendrocyte specification, differentiation, and myelination depending on timing and dosage (Xie et al, 2014). In support of this hypothesis, Wnt pathway activation was found to affect oligodendrocyte lineage cells in a dose-dependent fashion; low Wnt tone allows OPCs to differentiate and high Wnt tone after injury is associated with permanent WMI (Fancy et al, 2014).…”

Section: Restoring Function: Mediators Of Oligodendrocyte Regeneramentioning

confidence: 99%

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Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

et al. 2016

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Oligodendrocytes readily regenerate and replace myelin membranes around axons in the adult mammalian central nervous system (CNS) following injury. The ability to regenerate oligodendrocytes depends on the availability of neural progenitors called oligodendrocyte precursor cells (OPCs) in the adult CNS that respond to injury-associated signals to induce OPC expansion followed by oligodendrocyte differentiation, axonal contact and myelin regeneration (remyelination). Remyelination ensures the maintenance of axonal conduction, and the oligodendrocytes themselves provide metabolic factors that are necessary to maintain neuronal integrity. Recent advances in oligodendrocyte regeneration research are beginning to shed light on critical intrinsic signals, as well as extrinsic, environmental factors that regulate the distinct steps of oligodendrocyte lineage progression and myelin replacement under CNS injury. These studies may offer novel pharmacological targets for regenerative medicine in inflammatory demyelinating disorders in the CNS such as multiple sclerosis.

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Section: Restoring Function: Mediators Of Oligodendrocyte Regeneramentioning

confidence: 99%

Section: Restoring Function: Mediators Of Oligodendrocyte Regeneramentioning

confidence: 99%

Section: Restoring Function: Mediators Of Oligodendrocyte Regeneramentioning

confidence: 99%

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Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

et al. 2016

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“…For example, the capacity of ␤-catenin to modulate inflammatory and immune responses (71) could be related to its ability to modulate the expression of IFN-␤, which is a major regulator of immunity and inflammatory responses. Also, cross talk between ␤-catenin and IFN-␤ during the establishment and/or treatment of neurological disorders, such as Alzheimer's disease and multiple sclerosis, should be considered, since both the Wnt/␤-catenin pathway and the IFN-␤ response have been associated with these neurological pathologies (72)(73)(74). Although modulation of the constitutive level of IFN-␤ expression has probably been observed in the past by many researchers, it has often been neglected because it seemed to be only a minor response compared to pathogen-induced IFN-␤ expression.…”

Section: Licl Treatment Enhances Constitutive Ifn-␤ Gene Expressionmentioning

confidence: 99%

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Marcato

Luron

Laqueuvre

et al. 2016

Molecular and Cellular Biology

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. Rapid upregulation of IFN-␤ gene expression occurs after recognition of viral nucleic acids by pattern recognition receptors (PRRs) consisting of either cytosolic receptors, such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5), or membrane-associated Toll-like receptors, such as Toll-like receptor 3 (TLR3) (3). After sensing single-or doublestranded RNA of viral origin, these receptors activate signaling pathways, implicating the phosphorylation and nuclear translocation of several transcription factors, among which is interferon regulatory factor 3 (IRF3), rapidly leading downstream to a robust activation of expression of the IFN-␤ gene. After being secreted, the IFN-␤ protein binds to the type I interferon receptor and triggers the JAK-STAT1/2 signal transduction pathway. This pathway leads to the activation and inhibition of the expression of a large set of genes that constitute the type I IFN response mounted to antagonize viral infection at different levels (4).Mice lacking IFN-␤ (5) or the subunit of the type I interferon receptor (6, 7) are highly susceptible to viral infections. They succumb to sublethal doses of a variety of viruses, thus confirming the main role of IFN-␤ in the establishment of an innate antiviral response. However, beyond the antiviral response, IFN-␤ affects a wide range of other biological functions; for the most part, these are related to modulation of the immune (innate and adaptive) and inflammatory responses as well as to cell proliferation and differentiation. Even though IFN-␤ has been described to have an anti-inflammatory benefit, it has also been implicated in the development of several inflammatory and autoimmune diseases (8-10). Hence, the beneficial or detrimental outcome of IFN-␤ expression for the organism depends on the timing and kinetics of IFN-␤ synthesis and the amount of IFN-␤ being synthesized (11,12). If a marked activation of IFN-␤ gene expression is required to efficiently set up the appropriate response to an external aggression, such as virus infection, this response needs to be adjusted in order to limit its pathological side effects.As expected for a gene with pleiotropic functions, its transcriptional state is regulated at different levels. At the cellular level, only a stochastic fraction of the infected cells produces 14) as a way to avoid an exacerbated and uncontrolled IFN response. At the nuclear level, one IFN-␤ allele localizes within interchromosomal regions rich in NF-B DNA binding sites before and after infection (15), whereas the other allele localizes next to pericentromeric heterochromatin (PCH) clusters in the absence of infection and dissociates from PCH clusters during infection (16). The monoallelic characteristic of these particular subnuclear localizations suggests that a yet undeciphered regulatory mechanism exists at the chromosome level. Finally, at the promoter level, the coordinated action of several transcription factors and chromatin-remodeling complexes (17-21) regulates the...

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“…Wnt/β-catenin and Sonic HedgeHog (SHH) morphogen signallings both regulate embryonic neurogenesis and angiogenesis [123,124] and are variably associated with the remyelination process [125] and BBB integrity [126]. Nogo-A is an axonal growth inhibitor, and negative regulator of CNS angiogenesis [127]; anti-Nogo IgGs have been shown to suppress EAE through an immunomodulatory activity and the removal of remyelination obstacles between axons and new myelinating membranes [128].…”

Section: Other Angiogenic Molecules Potentially Involved In Ms and Eamentioning

confidence: 99%

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Girolamo

Coppola

Ribatti

et al. 2014

Acta Neuropathologica Communications

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Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood-brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

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Wnt Signaling in Remyelination in Multiple Sclerosis: Friend or Foe?

Cited by 44 publications

References 68 publications

Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

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