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: 15.05). 03/2010; 65(5):597-611. DOI: 10.1016/j.neuron.2010.01.027
Source: PubMed


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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Available from: Jason C Dugas, Apr 15, 2014
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    • "Depression of the neurogenic cascade, including miR-124-mediated regulation, may participate in the neurogenesis-to-gliogenesis switch. miR-219 stimulates both neurogenesis and gliogenesis during CNS development in the zebrafish (Hudish et al., 2013) and terminal differentiation of oligodendrocytes in the mouse (Dugas et al., 2010; Zhao et al., 2010). In our work, however, miR-219 OE only suppressed astrocytic differentiation of NSPCs in a limited developmental time window (Figures 1C–1F). "
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    ABSTRACT: Mammalian neural stem/progenitor cells (NSPCs) sequentially generate neurons and glia during CNS development. Here we identified miRNA-153 (miR-153) as a modulator of the temporal regulation of NSPC differentiation. Overexpression (OE) of miR-153 delayed the onset of astrogliogenesis and maintained NSPCs in an undifferentiated state in vitro and in the developing cortex. The transcription factors nuclear factor I (NFI) A and B, essential regulators of the initiation of gliogenesis, were found to be targets of miR-153. Inhibition of miR-153 in early neurogenic NSPCs induced precocious gliogenesis, whereas NFIA/B overexpression rescued the anti-gliogenic phenotypes induced by miR-153 OE. Our results indicate that miR-mediated fine control of NFIA/B expression is important in the molecular networks that regulate the acquisition of gliogenic competence by NSPCs in the developing CNS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 07/2015; 5(3). DOI:10.1016/j.stemcr.2015.06.006 · 5.37 Impact Factor
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    • "MiR-219 has been found to be significantly downregulated in HCC, and exert tumor-suppressive effects in hepatic carcinogenesis through negative regulation of GPC3 expression [15], which is consistent with our experimental results in HCC cell lines and tissues. Previous studies have shown that miR-219 inhibited cell proliferation [29,30]. There are several known pathways, including the GPC3 pathway by which the proliferation of HCC cells is regulated. "
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    ABSTRACT: Background To understand the involvement of structural maintenance of chromosome 4 (SMC4) in the development and progression of hepatocellular carcinoma (HCC). Methods Real-time quantitative PCR and Western Blotting were applied to measure the expression of SMC4 in HCC samples and cell lines. The tumor-promoting effect of SMC4 was determined by WST-1, soft agar colony formation, cell motility and invasion assays. The SMC4 target signal pathway was identified by luciferase reporter and real-time quantitative PCR assays. Results The upregulation of SMC4 was frequently detected in HCC samples and cell lines. Functional assays demonstrated that SMC4 could effectively promote tumor cell growth rate, colony formation in soft agar, wound-healing and invasion. Further studies showed that increased miR-219 levels caused a significant decrease in the SMC4 expression, and SMC4 inhibitor downregulated JAK2/Stat3 expression at both the mRNA and protein levels. Conclusions Our findings provide new insight into SMC4 function and the mechanisms of growth and invasion of HCC.
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    • "Studies using quantitative real time-PCR, microarray and northern blot technique have shown that miRNA expression alters during Schwann cell differentiation of precursor cells and subsequent myelination (Bremer et al., 2010; Verrier et al., 2010; Yun et al., 2010). After knocking out the Dicer1 gene (a key enzyme for miRNA biogenesis ), Schwann cells do not have the capacity to form myelin sheaths, while after silencing Dicer1 gene expression, these cells greatly proliferated and cannot form myelin sheath with normal function (Dugas et al., 2010; Pereira et al., 2010). These findings suggest that miRNAs likely regulate Schwann cell differentiation, myelination and peripheral nerve growth and development. "
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