Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region

Neurobiol Dis. 2015 May:77:106-16. doi: 10.1016/j.nbd.2015.02.021. Epub 2015 Mar 5.

Abstract

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.

Keywords: Cortical development; Cortical progenitor proliferation; Down syndrome; Neural cell death; Neurogenesis; Olig2.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Calbindins / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Death / genetics
  • Cerebral Cortex* / embryology
  • Cerebral Cortex* / growth & development
  • Cerebral Cortex* / pathology
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Down Syndrome / genetics*
  • Down Syndrome / pathology*
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental / genetics*
  • Homeodomain Proteins / metabolism
  • Interneurons / metabolism
  • Interneurons / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / genetics*
  • Nuclear Proteins / metabolism
  • Oligodendrocyte Transcription Factor 2
  • POU Domain Factors / metabolism
  • Parvalbumins / metabolism
  • Repressor Proteins / metabolism
  • Transcription Factors / metabolism
  • Trinucleotide Repeats / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calbindins
  • Carrier Proteins
  • Cell Cycle Proteins
  • CtIP protein, mouse
  • Cux1 protein, mouse
  • DNA-Binding Proteins
  • Etv1 protein, mouse
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • OLIG2 protein, human
  • Oligodendrocyte Transcription Factor 2
  • POU Domain Factors
  • Parvalbumins
  • Repressor Proteins
  • Transcription Factors
  • Pou3f3 protein, mouse