Altered migratory trajectories in cerebral organoids derived from individuals with neuronal heterotopia

Malformations of the human cortex represent a major cause of disability. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knock-out lines. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knock-down of their expression cause changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of periventricular heterotopia.