Stage-specific deletion of Olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes

J Neurosci. 2013 May 8;33(19):8454-62. doi: 10.1523/JNEUROSCI.2453-12.2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / genetics
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
  • Animals
  • Animals, Newborn
  • Arabidopsis Proteins / metabolism
  • Autophagy-Related Proteins
  • Basic Helix-Loop-Helix Transcription Factors / deficiency*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / ultrastructure
  • Bromodeoxyuridine / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cuprizone / toxicity
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Green Fluorescent Proteins / genetics
  • In Situ Nick-End Labeling
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intramolecular Transferases / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Monoamine Oxidase Inhibitors / toxicity
  • Myelin Basic Protein / metabolism
  • Myelin Proteolipid Protein / genetics
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / ultrastructure
  • Oligodendrocyte Transcription Factor 2
  • Oligodendroglia / drug effects
  • Oligodendroglia / physiology*
  • Transfection
  • ran GTP-Binding Protein / metabolism

Substances

  • Arabidopsis Proteins
  • Autophagy-Related Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Monoamine Oxidase Inhibitors
  • Myelin Basic Protein
  • Myelin Proteolipid Protein
  • Nerve Tissue Proteins
  • Olig1 protein, mouse
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Ran protein, mouse
  • Rb1cc1 protein, mouse
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Cuprizone
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases
  • ran GTP-Binding Protein
  • Intramolecular Transferases
  • marneral synthase, Arabidopsis
  • Bromodeoxyuridine