Conserved and Distinct Functions of the Autism-Related Chromatin Remodeler CHD8 in Embryonic and Adult Forebrain Neurogenesis

The chromatin remodeler CHD8 represents a high-confidence risk factor in autism, a multistage progressive neurologic disorder, how-ever the underlying stage-specific functions remain elusive. In this study, by analyzing Chd8 conditional knock-out mice (male and female), we find that CHD8 controls cortical neural stem/progenitor cell (NSC) proliferation and survival in a stage-dependent man-ner. Strikingly, inducible genetic deletion reveals that CHD8 is required for the production and fitness of transit-amplifying intermedi-ate progenitors (IPCs) essential for upper-layer neuron expansion in the embryonic cortex. p53 loss of function partially rescues apoptosis and neurogenesis defects in the Chd8-deficient brain. Further, transcriptomic and epigenomic profiling indicates that CHD8 regulates the chromatin accessibility landscape to activate neurogenesis-promoting factors including TBR2, a key regulator of IPC neu-rogenesis, while repressing DNA damage-and p53-induced apoptotic programs. In the adult brain, CHD8 depletion impairs forebrain neurogenesis by impeding IPC differentiation from NSCs in both subventricular and subgranular zones; however, unlike in embryos, it does not affect NSC proliferation and survival. Treatment with an antidepressant approved by the Federal Drug Administration (FDA), fluoxetine, partially restores adult hippocampal neurogenesis in Chd8-ablated mice. Together, our multistage functional studies identify temporally specific roles for CHD8 in developmental and adult neurogenesis, pointing to a potential strategy to enhance neu-rogenesis in the CHD8-deficient brain.