CHD2 is Required for Embryonic Neurogenesis in the Developing Cerebral Cortex

Abstract

Chromodomain helicase DNA-binding protein 2 (CHD2) has been associated with a broad spectrum of neurodevelopmental disorders, such as autism spectrum disorders and intellectual disability. However, it is largely unknown whether and how CHD2 is involved in brain development. Here, we demonstrate that CHD2 is predominantly expressed in Pax6 1 radial glial cells (RGs) but rarely expressed in Tbr2 1 intermediate progenitors (IPs). Importantly, the suppression of CHD2 expression inhibits the self-renewal of RGs and increases the generation of IPs and the production of neurons. CHD2 mediates these functions by directly binding to the genomic region of repressor element 1-silencing transcription factor (REST), thereby regulating the expression of REST. Furthermore, the overexpression of REST rescues the defect in neurogenesis caused by CHD2 knockdown. Taken together, these findings demonstrate an essential role of CHD2 in the maintenance of the RGs self-renewal levels, the subsequent generation of IPs, and neuronal output during neurogenesis in cerebral cortical development, suggesting that inactivation of CHD2 during neurogenesis might contribute to abnormal neurodevelopment.

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

“…Our findings suggest that in addition to critical functions during brain development, CHD2 may also be important in maintenance of adult brain function and integrity. Indeed, a relevant target of CHD2 is REST [60], which is an important regulator of neuronal gene expression during development, yet that also regulates stress-related gene expression in the aging brain [61]. REST levels fail to become upregulated in FTD, Alzheimer’s disease and dementia with Lewy bodies, like they are during healthy aging, suggesting that reduced REST levels may contribute to neurodegeneration.…”

CHD7 promotes proliferation of neural stem cells mediated by MIF

“…Chd4 was required for Ezh2 mediated inhibition of gliogenesis in mouse embryonic brain [27]. In addition, Chd2 was required for embryonic neurogenesis regulating REST and also expressed in cultured neurospheres in mouse [28]. Depletion of Chd5 led to an inhibition of neurogenesis accompanied with the accumulation of undifferentiated cells in the mouse embryonic brain [29].…”

A Novel Genetic Syndrome Caused by Haploinsufficiency of CHD2, a Regulator of Chromatin Structure

“…A recent study has shown that CHD2 plays a role in embryonic neurogenesis [21]. CHD2, primarily expressed in Pax6 positive radial glial cells, was found to maintain the self-renewal capacity of this cell population, increasing the generation of intermediate progenitors through direct binding to the repressor element 1-silencing transcription factor (REST) genomic region.…”