Human cerebral organoids reveal progenitor pathology in EML1‐linked cortical malformation

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Jabali, Ammar | Hoffrichter, Anne | Uzquiano, Ana | Marsoner, Fabio | Wilkens, Ruven | Siekmann, Marco | Bohl, Bettina | Rossetti, Andrea, C | Horschitz, Sandra | Koch, Philipp | Francis, Fiona | Ladewig, Julia

Edité par CCSD ; EMBO Press -

International audience. Malformations of human cortical development (MCD) can cause severe disabilities. The lack of human-specific models hampers our understanding of the molecular underpinnings of the intricate processes leading to MCD. Here, we use cerebral organoids derived from patients and genome edited-induced pluripotent stem cells to address pathophysiological changes associated with a complex MCD caused by mutations in the echinoderm microtubuleassociated protein-like 1 (EML1) gene. EML1-deficient organoids display ectopic neural rosettes at the basal side of the ventricular zone areas and clusters of heterotopic neurons. Single-cell RNA sequencing shows an upregulation of basal radial glial (RG) markers and human-specific extracellular matrix components in the ectopic cell population. Gene ontology and molecular analyses suggest that ectopic progenitor cells originate from perturbed apical RG cell behavior and yes-associated protein 1 (YAP1)-triggered expansion. Our data highlight a progenitor origin of EML1 mutation-induced MCD and provide new mechanistic insight into the human disease pathology.

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