ECB-ART-50432
EMBO Rep
2022 May 04;235:e54027. doi: 10.15252/embr.202154027.
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Human cerebral organoids reveal progenitor pathology in EML1-linked cortical malformation.
Jabali A
,
Hoffrichter A
,
Uzquiano A
,
Marsoner F
,
Wilkens R
,
Siekmann M
,
Bohl B
,
Rossetti AC
,
Horschitz S
,
Koch P
,
Francis F
,
Ladewig J
.
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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 microtubule-associated 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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