ATM-knockout on total and phosphorylation proteomes of cortical brain organoids

ATM (ataxia telangiectasia mutated) kinase is crucial to a wide range of human developmental disorders and adult/pediatric malignancies. Its mutations are causally tied to ataxia telangiectasia, a multi-systemic congenital disorder mainly affecting brain and blood systems. We generated 4 separate ATM-knockout human pluripotent stem cell lines and differentiated them to form 3-dimensional brain cortical brain organoids. Brain cortical organoids are an excellent model of human developing cortex. Using these analyses, we identified ATM-dependent phosphorylation predominantly influences factors in neurogenesis, neuronal differentiation, cell morphogenesis, and microtubule cytoskeleton as well as kinases involved in ATM, BNDF, and WNT signaling, G2/M checkpoint, and p53 regulation. These findings have broad implications about diseases associated with ATM, including ataxia telangiectasia.