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Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

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Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells. / Goncalves, Maria B.; Wu, Yue; Clarke, Earl et al.

In: The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 39, No. 16, 17.04.2019, p. 3013-3027.

Research output: Contribution to journalArticlepeer-review

Harvard

Goncalves, MB, Wu, Y, Clarke, E, Grist, J, Hobbs, C, Trigo, D, Jack, J & Corcoran, JPT 2019, 'Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells', The Journal of neuroscience : the official journal of the Society for Neuroscience, vol. 39, no. 16, pp. 3013-3027. https://doi.org/10.1523/JNEUROSCI.2922-18.2019

APA

Goncalves, M. B., Wu, Y., Clarke, E., Grist, J., Hobbs, C., Trigo, D., Jack, J., & Corcoran, J. P. T. (2019). Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(16), 3013-3027. https://doi.org/10.1523/JNEUROSCI.2922-18.2019

Vancouver

Goncalves MB, Wu Y, Clarke E, Grist J, Hobbs C, Trigo D et al. Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019 Apr 17;39(16):3013-3027. https://doi.org/10.1523/JNEUROSCI.2922-18.2019

Author

Goncalves, Maria B. ; Wu, Yue ; Clarke, Earl et al. / Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells. In: The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019 ; Vol. 39, No. 16. pp. 3013-3027.

Bibtex Download

@article{79c9bc95e5534427afff0ea2a28ad709,
title = "Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells",
abstract = "In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron-glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR-calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin-Ca2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.",
keywords = "Decorin, Exosome, Myelination, NG cells, RARα, RARβ, Retinoic acid",
author = "Goncalves, {Maria B.} and Yue Wu and Earl Clarke and John Grist and Carl Hobbs and Diogo Trigo and Julian Jack and Corcoran, {Jonathan P.T.}",
year = "2019",
month = apr,
day = "17",
doi = "10.1523/JNEUROSCI.2922-18.2019",
language = "English",
volume = "39",
pages = "3013--3027",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "16",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells

AU - Goncalves, Maria B.

AU - Wu, Yue

AU - Clarke, Earl

AU - Grist, John

AU - Hobbs, Carl

AU - Trigo, Diogo

AU - Jack, Julian

AU - Corcoran, Jonathan P.T.

PY - 2019/4/17

Y1 - 2019/4/17

N2 - In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron-glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR-calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin-Ca2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.

AB - In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron-glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR-calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin-Ca2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.

KW - Decorin

KW - Exosome

KW - Myelination

KW - NG cells

KW - RARα

KW - RARβ

KW - Retinoic acid

UR - http://www.scopus.com/inward/record.url?scp=85065027300&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2922-18.2019

DO - 10.1523/JNEUROSCI.2922-18.2019

M3 - Article

C2 - 30760627

AN - SCOPUS:85065027300

VL - 39

SP - 3013

EP - 3027

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 16

ER -

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