Notch1 control of oligodendrocyte differentiation in the spinal cord

Genoud, Stéphane; Lappe-Siefke, Corinna; Goebbels, Sandra; Radtke, Freddy; Aguet, Michel; Scherer, Steven S.; Suter, Ueli; Nave, Klaus‐Armin; Mantei, Ned

doi:10.1083/jcb.200202002

Cited by 193 publications

(180 citation statements)

References 80 publications

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“…Therefore, it is plausible that the neuronal-glial interaction facilitates the formation of an adhesion complex that is responsible for the integration of various chemical and mechanical factors regulating differentiation (31). This hypothesis could help explain how the axon can regulate differentiation through the expression of putative factors such as Jagged-1 (32,33) and Lingo-1 (34,35), as well as through its role in mechanotransduction. Because novel differentiation factors continue to be identified, it is essential to understand how a multitude of diverse extrinsic factors can be properly synthesized in the coordination of a single cell fate decision.…”

Section: Discussionmentioning

confidence: 99%

The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation

Rosenberg

Kelland

Tokar

et al. 2008

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

190

192

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The oligodendrocyte precursor cell (OPC) arises from the subventricular zone (SVZ) during early vertebrate development to migrate and proliferate along axon tracts before differentiating into the myelin-forming oligodendrocyte. We demonstrate that the spatial and temporal regulation of oligodendrocyte differentiation depends intimately on the axonal microenvironment and the density of precursor cells along a specified axonal area. Differentiation does not require dynamic axonal signaling, but instead is induced by packing constraints resulting from intercellular interactions. Schwann cells and even artificial beads bound to the axonal surface can mimic these constraints and promote differentiation. Together, these results describe the coordinately controlled biophysical interaction of oligodendrocyte precursors within an axonal niche leading to self-renewal and differentiation.myelination ͉ neuronal-glial interactions ͉ mechanotransduction D amage to the myelin membrane, as a result of nerve injury or disease, significantly impairs the ability of the nervous system to communicate and can lead to a host of debilitating symptoms, as well as an ultimate loss of function. In the CNS, demyelination is accompanied by the loss of oligodendrocytes, the terminally differentiated cells responsible for the formation of the myelin sheath. After the initial onset of demyelination, OPCs are induced to differentiate and remyelinate, effectively replacing lost oligodendrocytes. Unfortunately, the capacity for remyelination is limited, and ultimately fails in the presence of chronic demyelination. It remains unclear why the CNS cannot sustain this initial ability to repair the myelin sheath. One possible explanation is that adult OPCs eventually lose their ability to differentiate into remyelinating oligodendrocytes (1). It is plausible that the continuous presence of a demyelinating environment is responsible for inhibiting the differentiation process. If this supposition is true, then it is imperative to identify the environmental conditions conducive to the ongoing production of oligodendrocytes.Examining oligodendrocyte generation during development could prove useful for determining the role of the environment in the induction of differentiation. Developing OPCs are proliferative and self-renewing cells that originate in the SVZ and migrate along axons throughout the CNS. During development, an OPC must decide how many times it will divide, and where it will migrate. Also, an OPC must choose whether to remain as a precursor cell into adulthood or to differentiate into a myelinating oligodendrocyte. Such complex decisions are likely to be heavily influenced by the nature of the surrounding environment and by the behavior of neighboring cells. Based on these assumptions, it is our goal to identify the environmental factors that influence the decision of an OPC to differentiate into an oligodendrocyte. To accomplish this goal, we first looked at the developing rat spinal cord to examine the temporal regulation of oligodendrocy...

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Section: Discussionmentioning

confidence: 99%

The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation

Rosenberg

Kelland

Tokar

et al. 2008

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

190

192

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“…The generation of conditional Cdc42 mutant mice and Rac1 mutant mice have been described previously. Mice homozygous for the Cdc42 floxed allele (Cdc42 lox/lox ) were crossed with mice heterozygous for the Cdc42 floxed allele, which expressed the Cre recombinase under the control of the CNPase (Cnp-Cre ϩ Cdc42 lox/wt ) (Genoud et al, 2002;Lappe-Siefke et al, 2003;Saher et al, 2005) (Soriano, 1999) into control and mutant mice. Cnp-Cre is active in Ͼ70% of all oligodendroglial cells (Benninger et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

“…1 A). In the CNS, Cre is active in premyelinating oligodendrocytes and in some spinal motoneurons from embryonic day (E) 12 (Genoud et al, 2002). To identify the recombined cells, we bred the conditional LacZ allele from the ROSA26 reporter mouse (Soriano, 1999) into control and mutant mice.…”

Section: Recombination Of the Conditional Cdc42 Allele In The Cns Of mentioning

confidence: 99%

Cdc42 and Rac1 Signaling Are Both Required for and Act Synergistically in the Correct Formation of Myelin Sheaths in the CNS

Thurnherr¹,

Benninger²,

Wu³

et al. 2006

J. Neurosci.

125

123

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The formation of myelin sheaths in the CNS is the result of a complex series of events involving oligodendrocyte progenitor cell (OPC) proliferation, directed migration, and the morphological changes associated with axon ensheathment and myelination. To examine the role of Rho GTPases in oligodendrocyte biology, we have used a conditional tissue-specific gene-targeting approach. Ablation of Cdc42 in cells of the oligodendrocyte lineage did not affect OPC proliferation, directed migration, or in vitro differentiation, but it led to the formation of a unique and stage-specific myelination phenotype. This was characterized by the extraordinary enlargement of the inner tongue of the oligodendrocyte process and concomitant formation of a myelin outfolding as a result of abnormal accumulation of cytoplasm in this region. Ablation of Rac1 also resulted in the abnormal accumulation of cytoplasm in the inner tongue of the oligodendrocyte process, and we provide genetic evidence that rac1 synergizes with cdc42 in a gene dosage-dependent way to regulate myelination.

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“…The Notch-Jagged signaling pathway is important for the timing of myelination in the developing nervous system [84]. Prior to myelination, Notch1 receptors on OPCs interact with Jagged1 signals on axons, activating the canonical pathway that increases the downstream effecter Hes5.…”

Section: Notch Signalingmentioning

confidence: 99%

Remyelination Therapy for Multiple Sclerosis

Keough

Yong

2013

Neurotherapeutics

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Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin and axons. All therapeutics used to treat MS have been developed to target an overactive immune response, with aims to reduce disease activity. Chronic demyelinated axons are further prone to irreversible damage and death, and it is imperative that new therapies address this critical issue. Remyelination, the generation of new myelin in the adult nervous system, is an endogenous repair mechanism that restores function of denuded axons and delays their deterioration. Although remyelination can be extensive in some patients, the majority of cases limit repair only to the acute phase of disease. A significant current drive in new MS therapeutics is to identify targets that can promote remyelination by boosting endogenous oligodendrocyte precursor cells to form new myelin. Also, a number of inhibitory pathways have been identified in chronic MS lesions that prevent oligodendrocyte precursor cells from being properly recruited to demyelinated lesions or interfere with their differentiation to myelin-forming oligodendrocytes. In this review, we introduce the phenomenon of remyelination from the view of experimental models and studies in MS patients, describe a potential role in remyelination for currently available MS mediations, and discuss many avenues that are being actively studied to promote remyelination. The next frontier in MS therapeutics will supplement immunomodulation with agents that directly foster myelin repair, with aims to delay disease progression and recover lost neurological functions.

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Notch1 control of oligodendrocyte differentiation in the spinal cord

Cited by 193 publications

References 80 publications

The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation

The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation

Cdc42 and Rac1 Signaling Are Both Required for and Act Synergistically in the Correct Formation of Myelin Sheaths in the CNS

Remyelination Therapy for Multiple Sclerosis

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