CRISPR/Cas9-mediated knockout of IL1RAPL1 in stem cells highlights a role in neural cell migration during cortical development

Abstract

Abstract Genetic risk factors contribute to cortical developmental abnormalities observed in a range of neurodevelopmental disorders including autism and schizophrenia. Emerging evidence suggests that IL1RAPL1is a common risk gene across many neurodevelopmental disorders. We combined CRISPR gene editing with induced pluripotent stem cell derived neuronal and microglia model systems to study the function effects of a disease relevant deletion in IL1RAPL1. We investigated several key aspects of human cortical development ranging from radial glia extension, neuronal progenitor migration, excitatory synapse formation and synaptic pruning by microglia. We found that the IL1RAPL1 deletion restricted neural cell migration and excitatory synapse formation in our model system. These findings provide new insight into how rare genetic mutations in IL1RAPL1 can exert deleterious effects on the developing human cortex.