Article

Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination.

Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305-5125, USA.
Neuron (impact factor: 14.74). 03/2010; 65(5):597-611. DOI:10.1016/j.neuron.2010.01.027 pp.597-611
Source: PubMed

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.

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Keywords

coupling differentiation
 
critical role
 
differentiate
 
inhibition
 
mature miRNAs
 
myelinating OLs
 
OL differentiation
 
OL lineage
 
OL precursor cells
 
OLs
 
OPC proliferation
 
OPC-OL miRNA processing disrupts normal CNS myelination
 
PDGFRalpha
 
proliferating OPCs
 
proliferation arrest
 
rapid transition
 
regulating oligodendrocyte
 
rescues OL differentiation defects
 
total miRNA loss
 
ZFP238 proteins