Gene discovery in autism spectrum disorders (ASD) has accelerated rapidly, resulting in an extensive list of reliably associated genes. However, there is a gap between these genes and an understanding of the underlying biology1. Several lines of evidence have suggested that early neurogenesis is involved in ASD pathology. However, the broad relevance of these findings to ASD is unclear, highlighting the need for a large-scale functional screen of ASD genes during human neurogenesis. Experiments of this type are not possible in human tissue, and mammalian organismal model systems would be extraordinarily expensive.
Fortunately, however, the development of induced pluripotent stem cell technologies has enabled unprecedented access to cell types from the human brain. Additionally, advances in CRISPR-based genetics approaches and single-cell RNA sequencing technology have made it possible to rapidly screen for genes involved in neurogenesis and to characterize the corresponding transcriptional changes2.
In the current proposal, Jeremy Willsey and Martin Kampmann propose to simultaneously perturb high-confidence ASD risk genes in human neural progenitor cells during differentiation into cortical projection neurons to determine the extent to which ASD risk genes are involved in proliferation and differentiation during neurogenesis. After identifying specific genes involved in these processes, the group will conduct single-cell RNA sequencing to determine whether common molecular pathways underlie these perturbations, thereby generating testable hypotheses for future investigations of higher-order phenotypes.