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

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. Bongarzone, Q. Richard Lu

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)566-582.e5
JournalDevelopmental cell
Volume40
Issue number6
DOIs
StatePublished - Mar 27 2017

Keywords

  • Etv5
  • Lingo1
  • demyelinating injury
  • experimental autoimmune encephalomyelitis
  • gene regulatory network
  • miR-219
  • miR-338
  • microRNAs
  • myelination
  • remyelination

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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