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

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.

Laminar specific gene expression reveals differences in postnatal laminar maturation in mouse auditory, visual, and somatosensory cortex

“…This antibody was reported to recognize a single band of ∼55 kDa on Western blots using tissue lysates from mouse brain. Immunostaining patterns were observed in deep layers of mouse neocortex at early postnatal days (Li et al, ; Liu et al, ) and in olfactory bulb (Cave et al, ; Harrison, Parrish, & Monaghan, ).…”

OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

“…Loss-of-function studies showed that only Olig1 repressed the production of GABAergic interneurons (Furusho et al, 2006; Ono et al, 2008; Petryniak et al, 2007; Silbereis et al, 2014). Gain-of-function studies showed that overexpression of Olig2 promoted the production of GABAergic neurons (Liu et al, 2015). However, this finding is confounded by the fact that the overexpression and mis-expression of Olig2 in inappropriate cells and developmental stages caused massive cell death in the mouse brain (Liu et al, 2015).…”

Impact of siRNA targeting of β-catenin on differentiation of rat neural stem cells and gene expression of Ngn1 and BMP4 following in vitro hypoxic-ischemic brain damage

“…During ischemic brain injuries, β-catenin is important for the regulation of NSC proliferation and differentiation ( 8 – 10 ). Neurogenin 1 (Ngn1) is a downstream target gene of β-catenin, and previous studies have demonstrated that Ngn1 is important during the differentiation of NSCs into neurons ( 11 , 12 ). As a member of the bone morphogenetic protein (BMP) family, the synergy between BMP4 and β-catenin is important in determining the differentiation pathway of NSCs ( 13 , 14 ).…”