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

• DOI: 10.1016/j.devcel.2017.03.001
• Publication Date: 2017-03-27T19:40:04Z
• Authors: Haibo Wang; Ana Lis Moyano; Zhangyan Ma; Yaqi Deng; Yifeng Lin; Chuntao Zhao; Liguo Zhang; Minqing Jiang; Xuelian He; Zhixing Ma; Fanghui Lu; Mei Xin; Wenhao Zhou; Sung Ok Yoon; Ernesto R. Bongar...; Q. Richard Lu
• Keywords: Central Nervous System; Mice, Knockout; 0303 health sciences; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Membrane Proteins; Cell Differentiation; Nerve Tissue Proteins; Optic Nerve; Nerve Regeneration; Mice, Inbred C57BL; Disease Models, Animal; MicroRNAs; Oligodendroglia; 03 medical and health sciences; Lecithins; Disease Progression; Animals; Cell Lineage; Gene Deletion; Myelin Sheath; Demyelinating Diseases

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.