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.

Automated summary

This study identifies the stage-dependent functions of CHD8 in neurogenesis, including the regulation of neural stem/progenitor cell proliferation and survival, the production of transit-amplifying intermediate progenitors (IPCs), and the activation of neurogenesis-promoting factors. It also reveals that CHD8 controls chromatin accessibility to activate neurogenesis-promoting factors and repress apoptotic programs. In the adult brain, CHD8 depletion impairs neurogenesis but does not affect NSC proliferation and survival, and this impairment can be partially restored with fluoxetine treatment.