Human stem cell based models of neuronal migration provide insight into neurological disease pathogenesis and potential treatment

Neuronal migration defects (NMDs) are among the most common and severe brain abnormalities in humans. Lack of disease models in mice or in human cells has hampered the identification of underlying mechanisms. From patients with severe NMDs we generated iPSCs then differentiated neural progenitor cells (NPCs). On artificial extracellular matrix, patient-derived neuronal cells showed defective migration and impaired neurite outgrowth. From a cohort of 107 families with NMDs, sequencing identified two homozygous C-terminal truncating mutations in CTNNA2, encoding αN-catenin, one of three paralogues of the α-catenin family, involved in epithelial integrity and cell polarity. Patient-derived or CRISPR-targeted CTNNA2- mutant neuronal cells showed defective migration and neurite stability. Recombinant αN-catenin was sufficient to bundle purified actin and to suppress the actin-branching activity of ARP2/3. Small molecule inhibitors of ARP2/3 rescued the CTNNA2 neurite defect. Thus, disease modeling in human cells could be used to understand NMD pathogenesis and develop treatments for associated disorders.