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Nat Med. 2019 Apr;25(4):561-568. doi: 10.1038/s41591-019-0371-0. Epub 2019 Mar 11.

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

Author information

1
Max Planck Institute of Psychiatry, Munich, Germany.
2
Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
3
International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
4
Department of Biology, University of Naples Federico II, Naples, Italy.
5
Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand.
6
Institute of Stem Cell Research, Helmholtz Center Munich, Munich, Germany.
7
Institute of Stem Cell Research, iPSC Core Facility, Helmholtz Center Munich, Munich, Germany.
8
Ludwig Maximilian University, Munich, Germany.
9
Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. barbara_treutlein@eva.mpg.de.
10
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. barbara_treutlein@eva.mpg.de.
11
Technical University Munich, Department of Biosciences, Freising, Germany. barbara_treutlein@eva.mpg.de.
12
Max Planck Institute of Psychiatry, Munich, Germany. silvia_cappello@psych.mpg.de.

Abstract

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.

PMID:
30858616
DOI:
10.1038/s41591-019-0371-0

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