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

Abstract

Summary 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, pre-myelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities, and die due to seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination.

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

“…olig2 induces transcription factors that are required for the generation of mature, postmitotic oligodendrocytes, notably olig1, Sox-10, Nkx2.2, Nkx6.2, Ying Yang 1, and ZFP488 [18][19][20][21][22][23] . in counterbalance, transcription [24][25][26] .…”

“…MRF is specifically expressed by postmitotic oligodendrocytes and promotes rapid oPC differentiation into myelin basic protein-positive and myelin oligodendrocyte glycoprotein-positive oligodendrocytes [24] . in mice lacking MRF in the oligodendrocyte lineage, the initial differentiation of oPCs into pre-myelinating oligodendrocytes is unaffected; however, these pre-myelinating oligodendrocytes fail to express the majority of myelin genes and the mice display severe neurological abnormalities [24] . Furthermore, MRF is reported to be required for the maintenance of myelin in mature oligodendrocytes.…”

Identification of genes expressed by zebrafish oligodendrocytes using a differential microarray screen

“…For example, Gpr17, which was identified by comparing expression profiles of optic nerves isolated from wild-type and Olig1 mutant mouse embryos, encodes a G protein-coupled receptor that controls the timing of oligodendrocyte differentiation . Myelin gene regulatory factor (Mrf), which was first identified as gene model 98 expressed by postmitotic oligodendrocytes isolated from mouse forebrain (Cahoy et al, 2008), encodes a transcription factor necessary for expression of myelin genes (Emery et al, 2009).…”

Production and Use of Lentivirus to Selectively Transduce Primary Oligodendrocyte Precursor Cells for <em>In Vitro</em> Myelination Assays

“…24. Plate cells onto dry PDL coated plates at a density between 1 x 10 5 and 5 x 10 5 per 10 cm plate with in SATO media (10 ml) that contain ciliary neurotrophic factor (CNTF, 10 ng/ml), platelet derived growth factor (PDGF, 10 ng/ml,), neurotrophin 3 (NT3, 1 ng/ml), and forskolin (4.2 µg/ml) 2,12 . Culture OPCs at 37 °C, 8% CO 2.…”