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Tapping into the glial reservoir: cells committed to remaining uncommitted.

Chong SY, Chan JR - J. Cell Biol. (2010)

Bottom Line: The development and maturation of the oligodendrocyte requires a series of highly orchestrated events that coordinate the proliferation and differentiation of the oligodendrocyte precursor cell (OPC) as well as the spatiotemporal regulation of myelination.In recent years, widespread interest has been devoted to the therapeutic potential of adult OPCs scattered throughout the central nervous system (CNS).Cell-autonomous regulators of differentiation and the heterogeneous microenvironment of the developing and the adult CNS may provide coordinated inhibitory cues that ultimately maintain a reservoir of uncommitted glia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Zilkha Neurogenetic Institute, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
The development and maturation of the oligodendrocyte requires a series of highly orchestrated events that coordinate the proliferation and differentiation of the oligodendrocyte precursor cell (OPC) as well as the spatiotemporal regulation of myelination. In recent years, widespread interest has been devoted to the therapeutic potential of adult OPCs scattered throughout the central nervous system (CNS). In this review, we highlight molecular mechanisms controlling OPC differentiation during development and the implication of these mechanisms on adult OPCs for remyelination. Cell-autonomous regulators of differentiation and the heterogeneous microenvironment of the developing and the adult CNS may provide coordinated inhibitory cues that ultimately maintain a reservoir of uncommitted glia.

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Intrinsic and extrinsic mechanisms prevent the differentiation of OPCs to myelinating oligodendrocytes. These mechanisms act during development and in some cases after injury and disease. Solid arrows indicate contact-mediated interactions such as Jagged1 expressed on axons acting through Notch1 on OPCs, leading to the suppression of myelin genes via Hes5. Dashed arrows indicate secreted molecules such as CTGF from the neuron and Wnt from a yet-unidentified source. Although its ligand has not been determined, GPR17 expressed by OPCs is likely sensitive to environmental signals.
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fig2: Intrinsic and extrinsic mechanisms prevent the differentiation of OPCs to myelinating oligodendrocytes. These mechanisms act during development and in some cases after injury and disease. Solid arrows indicate contact-mediated interactions such as Jagged1 expressed on axons acting through Notch1 on OPCs, leading to the suppression of myelin genes via Hes5. Dashed arrows indicate secreted molecules such as CTGF from the neuron and Wnt from a yet-unidentified source. Although its ligand has not been determined, GPR17 expressed by OPCs is likely sensitive to environmental signals.

Mentions: One of the most fundamental questions in biology is whether it is possible to resolve pathological states by recapitulating development. The OPC is a prototypical cell for answering this question, as an abundant number of endogenous undifferentiated precursors exist in the adult nervous system. Additionally, the simplicity in the binary decision to become a terminally differentiated oligodendrocyte or remain a precursor cell reduces the complexity when addressing cell fate decisions. Making the commitment to differentiate during development is a complex process, as it requires the coordination of transcriptional machinery in conjunction with epigenetic regulation within the cell. Ongoing research has also provided evidence for the impact of extrinsic factors on OPC differentiation. Curiously, many of these environmental influences appear to be inhibitory in nature, with the axon delaying OPC differentiation rather than promoting it. Fig. 2 summarizes the molecular components discussed in this review, with all of them playing a role during developmental OPC differentiation, and many of these inhibitory factors, originating from both the axon and within the OPC itself, appear to prevent adult OPCs from reaching their potential to participate in myelin repair. Both contact-mediated cues and secreted factors participate in inhibiting differentiation, although there is still much to learn as to how these environmental signals converge upon intracellular pathways as well as transcriptional regulators responsible for maintaining OPCs in an undifferentiated state (Fig. 2).


Tapping into the glial reservoir: cells committed to remaining uncommitted.

Chong SY, Chan JR - J. Cell Biol. (2010)

Intrinsic and extrinsic mechanisms prevent the differentiation of OPCs to myelinating oligodendrocytes. These mechanisms act during development and in some cases after injury and disease. Solid arrows indicate contact-mediated interactions such as Jagged1 expressed on axons acting through Notch1 on OPCs, leading to the suppression of myelin genes via Hes5. Dashed arrows indicate secreted molecules such as CTGF from the neuron and Wnt from a yet-unidentified source. Although its ligand has not been determined, GPR17 expressed by OPCs is likely sensitive to environmental signals.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2819683&req=5

fig2: Intrinsic and extrinsic mechanisms prevent the differentiation of OPCs to myelinating oligodendrocytes. These mechanisms act during development and in some cases after injury and disease. Solid arrows indicate contact-mediated interactions such as Jagged1 expressed on axons acting through Notch1 on OPCs, leading to the suppression of myelin genes via Hes5. Dashed arrows indicate secreted molecules such as CTGF from the neuron and Wnt from a yet-unidentified source. Although its ligand has not been determined, GPR17 expressed by OPCs is likely sensitive to environmental signals.
Mentions: One of the most fundamental questions in biology is whether it is possible to resolve pathological states by recapitulating development. The OPC is a prototypical cell for answering this question, as an abundant number of endogenous undifferentiated precursors exist in the adult nervous system. Additionally, the simplicity in the binary decision to become a terminally differentiated oligodendrocyte or remain a precursor cell reduces the complexity when addressing cell fate decisions. Making the commitment to differentiate during development is a complex process, as it requires the coordination of transcriptional machinery in conjunction with epigenetic regulation within the cell. Ongoing research has also provided evidence for the impact of extrinsic factors on OPC differentiation. Curiously, many of these environmental influences appear to be inhibitory in nature, with the axon delaying OPC differentiation rather than promoting it. Fig. 2 summarizes the molecular components discussed in this review, with all of them playing a role during developmental OPC differentiation, and many of these inhibitory factors, originating from both the axon and within the OPC itself, appear to prevent adult OPCs from reaching their potential to participate in myelin repair. Both contact-mediated cues and secreted factors participate in inhibiting differentiation, although there is still much to learn as to how these environmental signals converge upon intracellular pathways as well as transcriptional regulators responsible for maintaining OPCs in an undifferentiated state (Fig. 2).

Bottom Line: The development and maturation of the oligodendrocyte requires a series of highly orchestrated events that coordinate the proliferation and differentiation of the oligodendrocyte precursor cell (OPC) as well as the spatiotemporal regulation of myelination.In recent years, widespread interest has been devoted to the therapeutic potential of adult OPCs scattered throughout the central nervous system (CNS).Cell-autonomous regulators of differentiation and the heterogeneous microenvironment of the developing and the adult CNS may provide coordinated inhibitory cues that ultimately maintain a reservoir of uncommitted glia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Zilkha Neurogenetic Institute, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
The development and maturation of the oligodendrocyte requires a series of highly orchestrated events that coordinate the proliferation and differentiation of the oligodendrocyte precursor cell (OPC) as well as the spatiotemporal regulation of myelination. In recent years, widespread interest has been devoted to the therapeutic potential of adult OPCs scattered throughout the central nervous system (CNS). In this review, we highlight molecular mechanisms controlling OPC differentiation during development and the implication of these mechanisms on adult OPCs for remyelination. Cell-autonomous regulators of differentiation and the heterogeneous microenvironment of the developing and the adult CNS may provide coordinated inhibitory cues that ultimately maintain a reservoir of uncommitted glia.

Show MeSH
Related in: MedlinePlus