The impact of autism spectrum disorder-risk genes on human neural stem cell proliferation and survival

The development of autism spectrum disorder (ASD) is strongly influenced by genetic factors. To navigate the large number of genes associated with the disorder, recent efforts have been directed towards finding functional convergence among ASD-risk genes. Within the biological processes commonly affected in ASD, cell proliferation is of particular interest, given the occurrence of brain volume anomalies in a significant subset of the ASD population. Since neural stem cells are key players in the expansion of neural cell pools throughout development, we hypothesized that a group of ASD-risk genes regulates neural stem cell behavior. When mutated, these genes may disrupt neural stem cell proliferation, differentiation, and survival during development, leading to an altered brain size, architecture and, thus, function. In our work, we selected a large panel of ASD-risk genes from the SFARI gene database. We then tested their role in neural stem cell behavior via a loss-of-function screen in human cerebral organoids. This high-throughput screen utilizes DNA barcodes to trace cell lineages and quantify clonal expansion. Our work allowed us to identify which of the targeted ASD-risk genes disrupts neural stem cell proliferation and survival. Next, with the use of transcriptomics and molecular techniques, we will investigate the cellular and molecular mechanisms in which our genes of interest are involved, and how their mutations affect neural stem cell fate. This research aims to enhance our understanding of neural stem cell proliferation and survival in brain development in ASD, providing valuable insights towards potential treatment strategies.