| Autor: |
Indra Niehaus, Michaela Wilsch-Bräuninger, Felipe Mora-Bermúdez, Mihaela Bobic- Rasonja, Velena Radosevic, Marija Milkovic-Perisa, Pauline Wimberger, Mariasavina Severino, Alexandra Haase, Ulrich Martin, Karolina Kuenzel, Kaomei Guan, Katrin Neumann, Noreen Walker, Evelin Schröck, Natasa Jovanov-Milosevic, Wieland B. Huttner, Nataliya Di Donato, Michael Heide |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.07.519435 |
| Popis: |
PathogenicACTBandACTG1gene variants, encoding the actin isoformsβCYA andγCYA, respectively, are frequently associated with theBaraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) that includes malformations of cortical development. Here we explore whether cerebral organoids grown from BWCFF-S patient-derived induced pluripotent stem cells can provide insight into the pathogenesis underlying the cortical malformations of these patients. Cerebral organoids expressing either anACTBor anACTG1gene variant, each with a point mutation resulting in a single amino acid substitution, are reduced in size, showing smaller ventricle-like structures with a thinner ventricular zone (VZ). This decrease in VZ- progenitors is associated with a striking change in the orientation of their cleavage plane from predominantly vertical (control) to predominantly horizontal (BWCFF-S), which is incompatible with increasing VZ-progenitor abundance. The underlying cause appears to be an altered subcellular tubulin localization due to the actin mutations that affects mitotic spindle positioning of VZ-progenitors in BWCFF-S. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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