Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation
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Nature Publishing Group
Abstract
In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown. Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis. In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE). We find that silencing Chi3l3 increases severity of EAE. We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature. Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis. © 2019, The Author(s).
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Animals, Beta-n-acetylhexosaminidases, Chitinase-3-like protein 1, Encephalomyelitis, autoimmune, experimental, Erbb receptors, Female, Hek293 cells, Hexosaminidases, Humans, Lectins, Map kinase signaling system, Mice, Neural stem cells, Oligodendroglia, Chitinase, Chitinase 3 like protein 1, Chitinase 3 like protein 3, Epidermal growth factor receptor, Focal adhesion kinase 2, Inhibitor of differentiation 2, Inhibitor of differentiation 4, Mitogen activated protein kinase 1, Mitogen activated protein kinase 3, Oligodendrocyte transcription factor 1, Oligodendrocyte transcription factor 2, Transcription factor, Transcription factor hes 5, Unclassified drug, Beta n acetylhexosaminidase, Chi3l1 protein, human, Chi3l3 protein, mouse, Chitotriosidase, Egfr protein, mouse, Lectin, Adult, Animal cell, Animal experiment, Animal model, Article, Autoimmune disease, Brain damage, Controlled study, Experimental autoimmune encephalomyelitis, Experimental model, Human, Human cell, In vitro study, In vivo study, Mouse, Nerve cell differentiation, Nervous system inflammation, Neural stem cell, Nonhuman, Oligodendrogenesis, Protein expression, Subventricular zone, Upregulation, Animal, Hek293 cell line, Mapk signaling, Metabolism