Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly

Dec 10, 2025EMBO reports

Miniature brain models with mutated actin genes show how cells cause small brain size

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Abstract

Cerebral organoids derived from individuals with Baraitser-Winter-CerebroFrontoFacial syndrome exhibit reduced size and altered progenitor cleavage orientation.

Cerebral organoids from patients with ACTB/ACTG1 mutations show a thinner ventricular zone due to fewer progenitor cells.
The orientation of the cleavage plane in ventricular zone progenitors shifts from predominantly vertical to mostly horizontal.
The horizontal cleavage plane orientation may hinder the increase in ventricular zone progenitor abundance and instead favors the generation of basal progenitors.
Cytoskeletal and structural irregularities in the apical region of BWCFF-S progenitors are associated with the change in cleavage plane orientation.
These findings contribute to understanding the cellular mechanisms linked to microcephaly in patients with actin mutations.

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Actins are cytoskeletal proteins that are essential for multiple cellular processes. Mutations in the ACTB and ACTG1 genes, encoding the ubiquitous beta- and gamma-cytoskeletal actin isoforms, respectively, cause a broad spectrum of neurodevelopmental disorders, with microcephaly as the most frequent one. To investigate the pathogenesis underlying this cortical malformation, we studied patient-derived cerebral organoids from induced pluripotent stem cells of individuals with the Baraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) carrying an ACTB/ACTG1 missense mutation. These organoids were reduced in size, showing a thinner ventricular zone (VZ) due to reduced VZ progenitor abundance. Strikingly, VZ progenitors in BWCFF-S cerebral organoids displayed a shift in the orientation of their cleavage plane from a predominantly vertical to a majoritarian horizontal orientation. The latter cleavage plane orientation is incompatible with increasing VZ progenitor abundance and instead promotes basal progenitor generation. Various cytoskeletal and morphological irregularities of BWCFF-S VZ progenitors, notably in the apical region, seemingly contribute to this change in cleavage plane orientation. Our results provide insight into the cell biological basis of the microcephaly associated with BWCFF-S caused by actin mutations.

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Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly

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