Researchers have shown how mutations in key actin genes can lead to abnormally small brains in children with Baraitser–Winter syndrome. Using lab-grown human brain organoids, the team found that these mutations alter the orientation of early brain progenitor cell divisions and deplete crucial stem cell populations, providing a cellular mechanism for the syndrome‑associated microcephaly.
A collaborative effort by scientists from the German Primate Center – Leibniz Institute for Primate Research, Hannover Medical School, and the Max Planck Institute of Molecular Cell Biology and Genetics has identified a cellular mechanism that helps explain microcephaly in Baraitser–Winter syndrome.
The rare developmental disorder is caused by missense mutations in the actin genes ACTB and ACTG1, which encode ubiquitous cytoplasmic actin isoforms that are central components of the cytoskeleton – the internal scaffold that shapes cells and supports intracellular transport.
To investigate how these mutations impair brain growth, the researchers generated induced pluripotent stem cells from skin cells donated by individuals with Baraitser–Winter syndrome and differentiated them into three‑dimensional cerebral organoids that model early human brain development. According to a summary from the German Primate Center and the study in EMBO Reports, organoids derived from patient cells were about one‑quarter smaller than those from healthy donors after roughly 30 days of growth, and the internal ventricle‑like regions, where progenitor cells give rise to early nerve cells, were also significantly reduced in size.
A detailed analysis of the organoids revealed a shift in neural stem and progenitor cell populations. The number of apical progenitor cells in the ventricular‑zone–like regions – the main progenitor pool that drives expansion of the cerebral cortex – was markedly reduced, while basal progenitors, which normally arise later in development, were relatively more abundant. The EMBO Reports paper links this change to altered cleavage‑plane orientation during mitosis: instead of predominantly vertical, right‑angle divisions that favor self‑renewal of apical progenitors, many divisions in mutant cells occurred horizontally or at oblique angles, promoting delamination and conversion into basal progenitors and thereby limiting brain growth.
"Our findings provide the first cellular explanation for microcephaly in people with the rare Baraitser–Winter syndrome," said Indra Niehaus, first author of the study and a research associate at Hannover Medical School, in statements released by the German Primate Center and associated news outlets.
High‑resolution and electron microscopy further showed subtle but consistent abnormalities at the ventricular surface of the organoids, including irregular cell shapes, increased protrusions between neighboring cells and unusually high levels of tubulin at cell junctions. Although the overall architecture of the tissue remained recognizable, the authors report that these cytoskeletal and morphological irregularities are likely sufficient to alter the orientation of cell division and increase the rate at which apical progenitors detach from the ventricular zone.
To confirm that the actin mutations themselves cause these defects, the team used CRISPR/Cas9 genome editing to introduce the same Baraitser–Winter–associated mutation into an otherwise healthy human stem cell line. Cerebral organoids grown from the edited cells reproduced the reduced size and progenitor cell abnormalities seen in patient‑derived organoids, supporting a direct causal link between the single‑gene mutation and disrupted early brain development.
"A single change in the cytoskeleton is sufficient to disrupt the course of early brain development," noted Michael Heide, group leader at the German Primate Center and senior author of the study, in the institute's press communication.
The work, published in EMBO Reports under the title "Cerebral organoids expressing mutant actin genes reveal cellular mechanism underlying microcephaly," underscores the value of brain organoids for modeling human neurodevelopmental disorders. According to comments from the research team, the findings may help clinicians better interpret and classify genetic variants in patients with suspected Baraitser–Winter syndrome. The authors also suggest that, while direct interventions during early fetal brain development would be highly challenging, future therapies that modulate interactions between actin and microtubules could, in principle, offer new avenues for treatment.
