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: 32.24). 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.
    Full-text · Article · Mar 2015 · Neuron
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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.
    Full-text · Article · Mar 2015 · Neuron
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    • "cultured progenitors also impaired differentiation (Emery et al., 2009). Among the most potent inducers of myelination in rodents are: thyroid hormone (TH) (Barres et al., 1994) and retinoic acid (Huang et al., 2011), which are ligands for receptors with the ability to bind DNA and modulate transcription. "
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    ABSTRACT: The recent years have been characterized by a surge of studies on the role of transcription factors and histone modifications in regulating the progression of progenitors into oligodendrocytes. This review summarizes this body of evidence and presents an integrated view of transcriptional networks and epigenetic regulators defining proliferating progenitors and their differentiation along the oligodendrocyte lineage. We suggest that transcription factors in proliferating progenitors have direct access to DNA, due to predominantly euchromatic nuclei. As progenitors differentiate, however, transcriptional competence is modulated by the formation of heterochromatin, which modifies the association of DNA with nucleosomal histones and renders the access of transcription factors dependent on the activity of epigenetic modulators. These concepts are delineated within the context of development, and the potential functional implications are discussed. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Preview · Article · Mar 2015 · Glia
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