Abstract
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.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
2',3'-Cyclic-Nucleotide Phosphodiesterases / genetics
-
2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
-
Age Factors
-
Animals
-
Animals, Newborn
-
Basic Helix-Loop-Helix Transcription Factors / genetics
-
Basic Helix-Loop-Helix Transcription Factors / metabolism
-
Brain / cytology
-
Cell Differentiation / drug effects
-
Cell Differentiation / physiology*
-
Cells, Cultured
-
Central Nervous System / growth & development
-
Central Nervous System / metabolism
-
DEAD-box RNA Helicases / genetics
-
DEAD-box RNA Helicases / metabolism*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Forkhead Transcription Factors
-
Gene Expression Profiling / methods
-
Gene Expression Regulation, Developmental / genetics
-
Green Fluorescent Proteins / genetics
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
MicroRNAs / genetics
-
MicroRNAs / metabolism*
-
Myelin Proteins / genetics
-
Myelin Proteins / metabolism
-
Myelin Sheath / metabolism*
-
Nerve Growth Factors / genetics
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism
-
Oligodendrocyte Transcription Factor 2
-
Oligodendroglia / drug effects
-
Oligodendroglia / physiology*
-
Oligonucleotide Array Sequence Analysis / methods
-
Optic Nerve / growth & development
-
Optic Nerve / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Receptor, Platelet-Derived Growth Factor alpha / genetics
-
Receptor, Platelet-Derived Growth Factor alpha / metabolism
-
Ribonuclease III / genetics
-
Ribonuclease III / metabolism*
-
S100 Calcium Binding Protein beta Subunit
-
S100 Proteins / genetics
-
SOXD Transcription Factors / genetics
-
SOXD Transcription Factors / metabolism
-
Sciatic Nerve / growth & development
-
Sciatic Nerve / metabolism
-
Stem Cells / drug effects
-
Stem Cells / physiology
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transfection
Substances
-
Basic Helix-Loop-Helix Transcription Factors
-
DNA-Binding Proteins
-
Forkhead Transcription Factors
-
FoxJ3 protein, mouse
-
MicroRNAs
-
Myelin Proteins
-
Nerve Growth Factors
-
Nerve Tissue Proteins
-
Olig2 protein, mouse
-
Oligodendrocyte Transcription Factor 2
-
S100 Calcium Binding Protein beta Subunit
-
S100 Proteins
-
SOXD Transcription Factors
-
Sox6 protein, mouse
-
Transcription Factors
-
enhanced green fluorescent protein
-
Green Fluorescent Proteins
-
Receptor, Platelet-Derived Growth Factor alpha
-
DICER1 protein, human
-
Ribonuclease III
-
2',3'-Cyclic-Nucleotide Phosphodiesterases
-
DEAD-box RNA Helicases