title: miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS.
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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ana Lis
authors.initials: AL
authors.lastname: Moyano
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Zhangyan
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Chuntao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Minqing
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Xuelian
authors.initials: X
authors.lastname: He
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Fanghui
authors.initials: F
authors.lastname: Lu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.affiliation: Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Bongarzone
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address: richard.lu@cchmc.org.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D054709:Lecithins / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D009900:Optic Nerve / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
chemical_list: C523678:LINGO1 protein, mouse; D054709:Lecithins; C000609357:MIRN219 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C000591274:Mirn338 microRNA, mouse; D009419:Nerve Tissue Proteins
keywords: Etv5; Lingo1; demyelinating injury; experimental autoimmune encephalomyelitis; gene regulatory network; miR-219; miR-338; microRNAs; myelination; remyelination