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

Wei Liu, Hui Zhou, Lei Liu, Chuntao Zhao, Yaqi Deng, Lina Chen, Laiman Wu, Nicole Mandrycky, Christopher T. McNabb, Yuanbo Peng, Perry N. Fuchs, Jie Lu, Volney Sheen, Mengsheng Qiu, Meng Mao, Q. Richard Lu

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)106-116
Number of pages11
JournalNeurobiology of Disease
Volume77
DOIs
StatePublished - May 1 2015

Keywords

  • Cortical development
  • Cortical progenitor proliferation
  • Down syndrome
  • Neural cell death
  • Neurogenesis
  • Olig2

ASJC Scopus subject areas

  • Neurology

Fingerprint

Dive into the research topics of 'Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region'. Together they form a unique fingerprint.

Cite this