Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination

Zhang, Yueting; Argaw, Azeb Tadesse; Gurfein, Blake T.; Zameer, Andleeb; Snyder, Brian; Ge, Changrong; Lü, Qing; Rowitch, David H.; Raine, Cedric S.; Brosnan, Celia F.; John, Gareth R.

doi:10.1073/pnas.0902834106

Cited by 185 publications

(210 citation statements)

References 33 publications

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“…in MS, Jagged is re-expressed in astrocytes at the borders of active lesions [35] . Conditional ablation of Notch from olig1-positive oligodendroglial cells results in accelerated remyelination after LPC-induced focal demyelination in the corpus callosum [36] . An earlier study using 2',3'-cyclic nucleotide phosphodiesterase promoter (CNP)-cre-driven deletion failed to show any effect on the rate of remyelination [37] .…”

Section: Notchmentioning

confidence: 96%

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

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Section: Notchmentioning

confidence: 96%

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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“…For example, the Notch1 receptor and its ligand, Jagged1, which regulate myelination during CNS development, were recently shown to similarly affect OPC differentiation during remyelination after lysolecithin injection into the CC (28). Several in vitro studies suggest that CXCR4-expressing OPCs exhibit chemotactic and maturational responses to CXCL12, which promotes their expression of myelin proteins and differentiation into oligodendrocytes (17,18).…”

Section: Discussionmentioning

confidence: 99%

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Patel

McCandless

Dorsey

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

209

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Multiple sclerosis is a neurodegenerative disease characterized by episodes of autoimmune attack of oligodendrocytes leading to demyelination and progressive functional deficits. Because many patients exhibit functional recovery in between demyelinating episodes, understanding mechanisms responsible for repair of damaged myelin is critical for developing therapies that promote remyelination and prevent disease progression. The chemokine CXCL12 is a developmental molecule known to orchestrate the migration, proliferation, and differentiation of neuronal precursor cells within the developing CNS. Although studies suggest a role for CXCL12 in oligodendroglia ontogeny in vitro, no studies have investigated the role of CXCL12 in remyelination in vivo in the adult CNS. Using an experimental murine model of demyelination mediated by the copper chelator cuprizone, we evaluated the expression of CXCL12 and its receptor, CXCR4, within the demyelinating and remyelinating corpus callosum (CC). CXCL12 was significantly up-regulated within activated astrocytes and microglia in the CC during demyelination, as were numbers of CXCR4+ NG2+ oligodendrocyte precursor cells (OPCs). Loss of CXCR4 signaling via either pharmacological blockade or in vivo RNA silencing led to decreased OPCs maturation and failure to remyelinate. These data indicate that CXCR4 activation, by promoting the differentiation of OPCs into oligodendrocytes, is critical for remyelination of the injured adult CNS.M ultiple sclerosis (MS), a progressive, neurodegenerative disease of the CNS, occurs most often in a relapsing/remitting form, in which a period of demyelination is followed by a period of functional recovery (1). The recovery stage involves remyelination via the migration and maturation of oligodendrocyte precursor cells (OPCs) (2). However, as the disease progresses, remyelination fails with continuous loss of function (3). Possible explanations for remyelination failure of intact axons include defects in OPC recruitment to the site of demyelination or in OPC differentiation into myelinating oligodendrocytes. Although studies indicate that both aspects of OPC biology are altered in MS (4, 5), the molecular mechanisms that orchestrate these processes within the adult CNS are incompletely understood.Studies in mice indicate that neural precursors that give rise to cells of oligodendrocytes lineage can be identified within the ventral half of the ventricular zones of all CNS regions by embryonic days 12-14 (E12-E14) via their expression of NG2 chondroitin sulfate proteoglycan (6). In the final stage of oligodendrocyte differentiation, which occurs primarily during the postnatal period (P4-P12), OPCs begin to express mature markers of oligodendrocytes including 2′3′-cyclic nucleotide phosphohydrolase (CNPase), myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG). Similar events occur during remyelination; NG2+ OPCs proliferate within subventricular zones, migrate to areas of demyelination, and differentiate ...

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“…First, remyelination can occur with great efficiency despite the expression of Notch in precursor cells and Jagged expression within the demyelinated environment [63,64]. Second, conditional ablation of Notch in precursors leads to no [63] or a relatively minor effect on remyelination efficiency [65]. Third, when mice with experimental autoimmune encephalomyelitis (a model of immune mediated demyelination) were treated with a γ-secretase inhibitor, MW167, which prevents Notch signaling, myelin repair and axonal survival were improved [66].…”

Section: Wnt Signalingmentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination

Cited by 185 publications

References 33 publications

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

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