Malformations of the human cortex represent a major cause of disability1. 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 conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor–ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes 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 (scRNA-seq) 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 PH.
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The scRNA-seq data used in this study have been deposited in the Gene Expression Omnibus under accession number GSE124031. All relevant accession codes are provided. Further details on the methods can be found in the Life Sciences Reporting Summary. Additional data that support the findings of this study are available from the corresponding author upon reasonable request.
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We thank the families participating in this study for their involvement. We thank Y. Lu for help generating the microRNAs, M. Karow and I. Buchsbaum for helping with experiments and fruitful discussions in the lab, T. Öztürk for excellent technical support, A. Weigert for organoid culture, J. Kageyama for helping with data processing, R. Snabel for helping with Smart-seq2 libraries, the Core Unit Flow Cytometry at the Zentrum für Infektionsmedizin (veterinary faculty of the University of Leipzig) and the Core Unit Qualitätsmanagement/Technologieplattform at the Sächsischer Inkubator für Klinische Translation (SIKT) in Leipzig for karyotyping. This work was supported by funding from the DFG CA1205/2-1 (S.C.), ForIPS (M.G.), by the Max Planck Society (S.C., B.T.), by the Boehringer Ingelheim Fonds (S.K.), by the Health Research Council of NZ and Curekids (S.P.R.) and by an ERC Starting Grant (B.T.).