miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS

• Published in: Developmental cell Vol. 40; no. 6; pp. 566 - 582.e5
• Main Authors: Wang, Haibo, Moyano, Ana Lis, Ma, Zhangyan, Deng, Yaqi, Lin, Yifeng, Zhao, Chuntao, Zhang, Liguo, Jiang, Minqing, He, Xuelian, Ma, Zhixing, Lu, Fanghui, Xin, Mei, Zhou, Wenhao, Yoon, Sung Ok, Bongarzone, Ernesto R., Lu, Q. Richard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2017
• Subjects: Animals; Cell Differentiation - drug effects; Cell Lineage - drug effects; Central Nervous System - drug effects; Central Nervous System - metabolism; Central Nervous System - pathology; Demyelinating Diseases - genetics; Demyelinating Diseases - pathology; demyelinating injury; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - pathology; Etv5; experimental autoimmune encephalomyelitis; Gene Deletion; gene regulatory network; Lecithins - pharmacology; Lingo1; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mice, Knockout; microRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-219; miR-338; Multiple Sclerosis - genetics; Multiple Sclerosis - pathology; Multiple Sclerosis - therapy; Myelin Sheath - drug effects; Myelin Sheath - metabolism; Myelin Sheath - pathology; myelination; Nerve Regeneration - drug effects; Nerve Regeneration - genetics; Nerve Tissue Proteins - metabolism; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Optic Nerve - pathology; Optic Nerve - ultrastructure; Phenotype; remyelination; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology; Wound Healing - drug effects; Wound Healing - genetics; microRNAs; experimental autoimmune encephalomyelitis; Lingo1; myelination; miR-338; gene regulatory network; miR-219; remyelination; demyelinating injury; Etv5
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2017.03.001

A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair. [Display omitted] •miR-219 is critical for oligodendrocyte differentiation and myelination in murine CNS•miR-338 deletion exacerbates the dysmyelination phenotype in miR-219-deficient mice•miR-219 targets stage-specific inhibitors and Lingo1-Etv5 to promote CNS myelination•miR-219 mimics augment remyelination and functional recovery in demyelinating models Wang et al. show that miR-219 collaborates with miR-338 and is required for proper oligodendrocyte differentiation and myelination in the mammalian CNS by targeting a network of stage-specific differentiation inhibitors, including Lingo1 and Etv5. Therapeutic delivery of miR-219 also enhances myelin repair in animal models of multiple sclerosis.