Molecular and network disruptions in neurodevelopment uncovered by single cell transcriptomics analysis ofCHD8heterozygous cerebral organoids

Abstract

About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of ∼1000 genes that may be involved. The new challenge now is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we use single cell RNA-seq analysis to study one of the top risk gene,CHD8, in cerebral organoids, which models early neural development. We identify 21 cell clusters in the organoid samples, representing non-neuronal cells, neural progenitors, and early differentiating neurons at the start of neural cell fate commitment. Comparisons of the cells with one copy of theCHD8knockout and their isogenic controls uncover thousands of differentially expressed genes, which are enriched with function related to neural and brain development, with genes and pathways previously implicated in ASD, but surprisingly not for Schizophrenia and intellectual disability risk genes. The comparisons also find cell composition changes, indicating potential altered neural differential trajectories uponCHD8reduction. Moreover, we find that cell-cell communications are affected in theCHD8knockout organoids, including the interactions between neural and glial cells. Taken together, our results provide new data for understanding CHD8 functions in the early stages of neural lineage development and interaction.

CHD8 adulthood microglial knockout induces behavioral, morphological, and transcriptional changes in a sex-dependent manner

“…Therefore, CHD8 knockout induced an activation of microglia. In a separate study of CHD8 knockdown in human cerebral organoids, Astorkia et al demonstrated that CDH8 reduction leads to impaired neuronal-glial communication 63 . The decrease in number of microglia, in comparison to the activation of microglia, is more difficult to interpret.…”