Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination.
To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs (miR-219, miR-138, and miR-338) that are induced 10-100x during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRalpha, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs.
Dugas
Jason C
JC
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305-5125, USA. jcdugas@alum.mit.edu
Cuellar
Trinna L
TL
Scholze
Anja
A
Ason
Brandon
B
Ibrahim
Adiljan
A
Emery
Ben
B
Zamanian
Jennifer L
JL
Foo
Lynette C
LC
McManus
Michael T
MT
Barres
Ben A
BA
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009900:Optic Nerve / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000254:growth & development / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D051792:Basic Helix-Loop-Helix Proteins; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D049452:Green Fluorescent Proteins; D035683:MicroRNAs; D009185:Myelin Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D020796:Receptor, Platelet-Derived Growth Factor alpha; D043244:Ribonuclease III; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D055755:SOXD Transcription Factors; D014157:Transcription Factors; C503717:FoxJ3 protein, mouse; C512773:Olig2 protein, mouse; C095939:Sox6 protein, mouse; C485184:enhanced green fluorescent protein; C408087:DICER1 protein, human