PT  - JOURNAL ARTICLE
AU  - Maria B. Goncalves
AU  - Yue Wu
AU  - Earl Clarke
AU  - John Grist
AU  - Carl Hobbs
AU  - Diogo Trigo
AU  - Julian Jack
AU  - Jonathan P.T Corcoran
TI  - Regulation of myelination by exosome associated retinoic acid release from NG2-positive cells
AID  - 10.1523/JNEUROSCI.2922-18.2019
DP  - 2019 Feb 13
TA  - The Journal of Neuroscience
PG  - 2922-18
4099  - http://www.jneurosci.org/content/early/2019/02/12/JNEUROSCI.2922-18.2019.short
4100  - http://www.jneurosci.org/content/early/2019/02/12/JNEUROSCI.2922-18.2019.full
AB  - In the central nervous system, 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 (RAR) β signalling in remyelination. Using a male Sprague-Dawley rat model of PNS-CNS injury, we show that oral treatment with an RARβ agonist induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+cells) in a decorin mediated neuron-glia crosstalk. Decorin promoted the activation of RARα in NG2+cells, by increasing the availability of the endogenous ligand retinoic acid (RA). NG2+cells synthesise 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 signalling 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 STATEMENTThis study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock down experiments show that the retinoic acid (RA) signalling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross-talk between neuronal Retinoic acid receptor (RAR)β 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 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.