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

Johannes Klaus, Sabina Kanton, Christina Kyrousi, Ane Cristina Ayo-Martin, Rossella Di Giaimo, Stephan Riesenberg, Adam C. O’Neill, J. Gray Camp, Chiara Tocco, Malgorzata Santel, Ejona Rusha, Micha Drukker, Mariana Schroeder, Magdalena Götz, Stephen P. Robertson, Barbara Treutlein, Silvia Cappello

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

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.

Original languageEnglish
Pages (from-to)561-568
Number of pages8
JournalNature Medicine
Volume25
Issue number4
DOIs
StatePublished - 1 Apr 2019

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