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.

Defects in neurogenesis alter brain circuit formations and may lead to neurodevelopmental disorders such as autism and schizophrenia. Histone H2A.z, a variant of histone H2A, plays critical roles in chromatin structure and epigenetic regulation, but its function and mechanism in brain development remain largely unknown. Here, we find that the deletion of H2A.z results in enhanced proliferation of neural progenitors but reduced neuronal differentiation. In addition, neurons in H2A.z knockout mice exhibit abnormal dendrites during brain development. Furthermore, H2A.zcKO mice exhibit serial behavioral deficits, such as decreased exploratory activity and impaired learning and memory. Mechanistically, H2A.z regulates embryonic neurogenesis by targeting Nkx2–4 through interaction with Setd2, thereby promoting H3K36me3 modification to activate the transcription of Nkx2–4. Furthermore, enforced expression of Nkx2–4 can rescue the defective neurogenesis in the H2A.z-knockdown embryonic brain. Together, our findings implicate the epigenetic regulation by H2A.z in embryonic neurogenesis and provide a framework for understanding how disruption in the H2A.z gene may contribute to neurological disorders.