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

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 (RAR beta) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RAR beta agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG(2+) cells) in a decorin-mediated neuron- glia cross talk. Decorin promoted the activation of RAR alpha in NG(2+) cells by increasing the availability of the endogenous ligand RA. NG(2+) 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 RAR alpha signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RAR beta and RAR alpha are important regulators of oligodendrocyte differentiation, providing new targets for myelination.