GSE124031
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. Overall design: Single cell transcriptomes from human control and mutant organoids were analyzed in this study. Mutant organoids were generated from patient-derived iPSCs and carry mutations in the cadherin receptor-ligand pair DCHS1 and FAT4. Data were generated from dissected regions of 3 organoids per condition and processed using the SmartSeq2 approach. Additionally, 2d cultured neurons differentiated from control and mutant iPS cells were profiled using 10X Genomics 3' single cell transcriptome technology.