The Role of Chd3 in Murine Cortical Development

Abstract

The nucleosome remodeling and deacetylase (NuRD) complex makes use of Chromodomain Helicase DNA binding protein 3 (CHD3) to remodel chromatin. Of the three CHD proteins NuRD may incorporate (CHD3/4/5); the function of CHD3 within the brain is the only one to have not been studied through gene knockout. Chd3 mutations in humans cause a neurodevelopmental disorder (SNIBCPS) characterized by intellect and speech deficits, but limited work has been done to describe a phenotype in mice. We have generated mice with forebrain specific deletion of Chd3 to characterize its impact on embryonic and postnatal cortical development. To analyze the consequence of Chd3 ablation on cortical lamination, layer-specific staining was performed and showed a decreased number of cells in layers II-IV. Neuronal birthdating has demonstrated that this is due to a defect in migration, causing the cells to be retained in the lower layers. Behaviour testing has also indicated defect in fear learning and memory in heterozygote males. These initial indications of defects in cortical development and behavioural deficits in the Chd3 mutant mice suggest that the animals are a good first model of the SNIBCP syndrome.