title: Stage-specific deletion of Olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes.
abstract: The temporal and spatial patterning involved in the specification, differentiation, and myelination by oligodendroglia is coordinated in part by the activation and repression of various transcriptional programs. Olig2 is a basic helix-loop-helix transcription factor necessary for oligodendroglial development and expressed continuously throughout the lineage. Despite evidence for the critical role of Olig2 in oligodendroglial specification and differentiation, the function for Olig2 during later stages of oligodendroglial development, namely, the transition into mature oligodendrocytes (OLs) and the formation of the myelin sheath, remains unclear. To address the possibility for a stage-specific role, we deleted Olig2 in oligodendrocyte precursor cells (OPCs) under the control of the CNPase-promoter or in immature OLs under the inducible proteolipid protein promoter. As expected, ablation of Olig2 in OPCs significantly inhibits differentiation, resulting in hypomyelination. However, deletion of the Olig2 gene in immature OLs significantly enhances the maturation process and accelerates the kinetics of myelination/remyelination. Underlying the stage-specific roles for Olig2 is the compensatory expression and function of Olig1, a transcription factor that promotes OL maturation and (re)myelination. Olig1 expression is significantly reduced upon Olig2 deletion in OPCs but is dramatically increased by nearly threefold when deleted in immature OLs. By enforcing expression of Olig1 into OPCs in a null Olig2 background, we demonstrate that overexpression of Olig1 is sufficient to rescue the differentiation phenotype and partially compensates for the Olig2 deletion in vitro. Our results suggest a stage-specific regulatory role for Olig2, mediated by Olig1 that conveys opposing functions on the differentiation and maturation of oligodendrocytes.
authors: Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
authors: Feng
authors: F
authors: Mei
authors: Hongkai
authors: H
authors: Wang
authors: Shubao
authors: S
authors: Liu
authors: Jianqin
authors: J
authors: Niu
authors: Lingyun
authors: L
authors: Wang
authors: Yangtao
authors: Y
authors: He
authors: Ainhoa
authors: A
authors: Etxeberria
authors: Jonah R
authors: JR
authors: Chan
authors: Lan
authors: L
authors: Xiao
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D029681:Arabidopsis Proteins / Q000378:metabolism; D000071183:Autophagy-Related Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019751:Intramolecular Transferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D029681:Arabidopsis Proteins; D000071183:Autophagy-Related Proteins; D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D003471:Cuprizone; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019751:Intramolecular Transferases; D008996:Monoamine Oxidase Inhibitors; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D020931:ran GTP-Binding Protein; C494786:Olig1 protein, mouse; C512773:Olig2 protein, mouse; C102460:Ran protein, mouse; C428743:Rb1cc1 protein, mouse; C485184:enhanced green fluorescent protein; C568454:marneral synthase, Arabidopsis
references: Curr Biol. 2002 Jul 9;12(13):1157-63
references: 12121626
references: J Neurosci. 2003 Oct 22;23(29):9547-56
references: 14573534
references: Brain. 2011 Jul;134(Pt 7):1882-900
references: 21507994
references: Development. 2004 May;131(10):2349-58
references: 15102707
references: Neurotherapeutics. 2012 Apr;9(2):422-45
references: 22173726
references: Mech Dev. 2000 Dec;99(1-2):143-8
references: 11091082
references: Neuron. 2000 Feb;25(2):317-29
references: 10719888
references: Annu Rev Neurosci. 2011;34:21-43
references: 21692657
references: Nucleic Acids Res. 2011 Mar;39(4):1280-93
references: 20959288
references: Neuron. 2001 Mar;29(3):603-14
references: 11301021
references: Neuron. 2000 Feb;25(2):331-43
references: 10719889
references: Development. 2007 May;134(10):1887-99
references: 17428828
references: Science. 2004 Dec 17;306(5704):2111-5
references: 15604411
references: Dev Biol. 2002 Aug 15;248(2):356-68
references: 12167410
references: Neuron. 2011 Mar 10;69(5):918-29
references: 21382552
references: Dev Biol. 2007 Feb 15;302(2):683-93
references: 17098222
references: J Neurosci Res. 2009 Nov 15;87(15):3438-46
references: 19739249
references: Stem Cells. 2006 Apr;24(4):1001-10
references: 16253982
references: Glia. 2011 Jul;59(7):1094-106
references: 21538562
references: Neuron. 2004 Jul 22;43(2):183-91
references: 15260955
references: Mol Biol Rep. 2011 Oct;38(7):4637-42
references: 21132377
references: PLoS One. 2010 Dec 29;5(12):e15741
references: 21206754
references: Glia. 2006 Jul;54(1):1-10
references: 16652341
references: Physiol Rev. 2001 Apr;81(2):871-927
references: 11274346
references: Cell. 2002 Apr 5;109(1):75-86
references: 11955448
references: Glia. 2003 Dec;44(3):264-74
references: 14603467
references: Genesis. 2003 Jan;35(1):63-72
references: 12481300
references: Nat Neurosci. 2001 Oct;4(10):973-4
references: 11574831
references: BMC Neurosci. 2009 Sep 22;10:117
references: 19772605
references: Genes Dev. 2002 Jan 15;16(2):165-70
references: 11799060
references: Glia. 2012 Sep;60(9):1427-36
references: 22639060
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7853-8
references: 16682644
references: Development. 2006 Sep;133(17):3389-98
references: 16908628
references: Lancet Neurol. 2005 Feb;4(2):80
references: 15709220
references: Cell. 2002 Apr 5;109(1):61-73
references: 11955447
references: Science. 2010 Nov 5;330(6005):779-82
references: 21051629
references: J Neurosci. 2007 Dec 26;27(52):14375-82
references: 18160645
references: J Neurosci. 2005 Feb 9;25(6):1354-65
references: 15703389
references: J Neurosci. 2005 Sep 7;25(36):8311-21
references: 16148239
references: Development. 2000 Jul;127(14):2989-98
references: 10862737
references: Biochim Biophys Acta. 2011 Feb;1812(2):184-93
references: 20887785
references: J Neurosci. 2006 Jan 25;26(4):1275-80
references: 16436615