How can loss of just one copy of a gene lead to a whole host of neurodevelopmental disorders (NDDs)? Around 25% of autism spectrum disorder (ASD) are caused by disrupting a single copy of one gene, yet disease-causing pathways remain elusive. The BAF (SWI/SNF) chromatin remodeling complex controls DNA accessibility and is necessary for all stages of brain development. BAF is a modular complex with multiple subunits associated with ASD in a dose-dependent way. We will study one of its scaffold proteins that emerges as a significant ASD risk gene. Significant challenges remain for generating physiologically relevant, whole body or human disease models to uncover molecular mechanisms that drive ASD. Our interdisciplinary team aims to tackle the central question of why partial loss of this BAF scaffold leads to ASD. Our team has experience generating physiologically relevant disease mouse models, differentiating tightly controlled populations of human pluripotent stem cell (hPSC)-derived neural progenitors and neurons, and has established rigorous biochemical assays to tackle molecular function of the BAF complex. We propose to address gene dosage, cell type specificity, and developmental stage for these risk genes using in vivo disease-relevant models and ex vivo human-relevant models. Completion of this work will increase our understanding of why NDDs are dose sensitive and identify cell-types and gene regulatory networks that cause them.