NG2 expression in NG2 glia is regulated by binding of SoxE and bHLH transcription factors to a Cspg4 intronic enhancer

Glia. 2018 Dec;66(12):2684-2699. doi: 10.1002/glia.23521. Epub 2018 Oct 10.

Abstract

NG2 is a type 1 integral membrane glycoprotein encoded by the Cspg4 gene. It is expressed on glial progenitor cells known as NG2 glial cells or oligodendrocyte precursor cells that exist widely throughout the developing and mature central nervous system and vascular mural cells but not on mature oligodendrocytes, astrocytes, microglia, neurons, or neural stem cells. Hence NG2 is widely used as a marker for NG2 glia in the rodent and human. The regulatory elements of the mouse Cspg4 gene and its flanking sequences have been used successfully to target reporter and Cre recombinase to NG2 glia in transgenic mice when used in a large 200 kb bacterial artificial chromosome cassette containing the 38 kb Cspg4 gene in the center. Despite the tightly regulated cell type- and stage-specific expression of NG2 in the brain and spinal cord, the mechanisms that regulate its transcription have remained unknown. Here, we describe a 1.45 kb intronic enhancer of the mouse Cspg4 gene that directed transcription of EGFP reporter to NG2 glia but not to pericytes in vitro and in transgenic mice. The 1.45 kb enhancer contained binding sites for SoxE and basic helix-loop-helix transcription factors, and its enhancer activity was augmented cooperatively by these factors, whose respective binding elements were found in close proximity to each other. Mutations in these binding elements abrogated the enhancer activity when tested in the postnatal mouse brain.

Keywords: Ascl1; Cspg4; NG2; Olig2; Sox10; oligodendrocyte precursor cell.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Antigens / genetics*
  • Antigens / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Binding Sites / genetics
  • Brain / cytology
  • Chromatin Immunoprecipitation
  • Enhancer Elements, Genetic / genetics*
  • Gene Expression Regulation, Developmental / genetics*
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Histones / metabolism
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Mutation / genetics
  • Neuroglia / metabolism*
  • Oligodendrocyte Transcription Factor 2 / genetics
  • Oligodendrocyte Transcription Factor 2 / metabolism
  • Proteoglycans / genetics*
  • Proteoglycans / metabolism*
  • SOXE Transcription Factors / genetics
  • SOXE Transcription Factors / metabolism
  • Transfection

Substances

  • Antigens
  • Basic Helix-Loop-Helix Transcription Factors
  • Glial Fibrillary Acidic Protein
  • Histones
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Proteoglycans
  • SOXE Transcription Factors
  • Sox10 protein, mouse
  • chondroitin sulfate proteoglycan 4
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins