Article

Myelin Gene Regulatory Factor Is a Critical Transcriptional Regulator Required for CNS Myelination

Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305-5125, USA.
Cell (Impact Factor: 33.12). 08/2009; 138(1):172-85. DOI: 10.1016/j.cell.2009.04.031
Source: PubMed

ABSTRACT The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named myelin gene regulatory factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, premyelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities and die because of seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination.

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    • "Our studies indicate that mutant Htt affects mature oligodendrocytes to cause a decrease in myelin proteins and subsequent loss of myelin, suggesting that the production of myelin proteins in mature oligodendrocytes is important for the maintenance of myelin in adult brains as well (Koenning et al., 2012). This idea is also supported by the finding that mutant Htt does not reduce Olig2 but rather affects the function of MYRF, which is expressed only in postmitotic oligodendrocytes (Cahoy et al., 2008; Emery et al., 2009; McKenzie et al., 2014). The findings of our study therefore suggest that improving the function of mature oligodendrocytes should at least be beneficial in HD and perhaps other age-dependent neurodegenerative diseases that involve the dysfunction of mature oligodendrocytes and associated axonal dysfunction as well. "
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    ABSTRACT: Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington's disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remains unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knockin mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6):1212-26. DOI:10.1016/j.neuron.2015.02.026 · 15.98 Impact Factor
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    • "Our studies indicate that mutant Htt affects mature oligodendrocytes to cause a decrease in myelin proteins and subsequent loss of myelin, suggesting that the production of myelin proteins in mature oligodendrocytes is important for the maintenance of myelin in adult brains as well (Koenning et al., 2012). This idea is also supported by the finding that mutant Htt does not reduce Olig2 but rather affects the function of MYRF, which is expressed only in postmitotic oligodendrocytes (Cahoy et al., 2008; Emery et al., 2009; McKenzie et al., 2014). The findings of our study therefore suggest that improving the function of mature oligodendrocytes should at least be beneficial in HD and perhaps other age-dependent neurodegenerative diseases that involve the dysfunction of mature oligodendrocytes and associated axonal dysfunction as well. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington's disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remains unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knockin mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target.
    Neuron 03/2015; 85(6):1212-1226. DOI:10.1016/j.neuron.2015.02.026. · 15.98 Impact Factor
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    • "That the Smad3 −/− phenotype is the more severe might be attributable to complete versus partial ablation of Tgfβ/Activin Smad-dependent signaling. The compensation seen in both genotypes also follows a precedent in other models displaying deficits in oligodendrocyte development and/or myelination (Montag et al., 1994; Larsen et al., 2006; Lewallen et al., 2011), although recovery is not a universal outcome (Meyerheim et al., 2004; Nolan et al., 2005; Emery et al., 2009). Our findings are also compatible with data from previous studies in mutants for MAP kinase components (Schwammenthal et al., 2004; Fyffe-Maricich et al., 2011). "
    Journal of Cell Science 06/2014; 127(13):e1-e1. DOI:10.1242/jcs.157677 · 5.33 Impact Factor
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