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  3. A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in cortical organoids

A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in cortical organoids

  • iScience. 2025 Jan 20;28(2):111853. doi: 10.1016/j.isci.2025.111853.
Jessica Honorato Ribeiro 1 2,  Emre Etlioglu 1,  Jasmine Buset 1,  Ann Janssen 1,  Hanne Puype 3 4 5,  Lisa Berden 1 6,  André Claude Mbouombouo Mfossa 1,  Winnok H De Vos 7,  Vanessa Vermeirssen 3 4 5,  Sarah Baatout 1 2,  Nicholas Rajan 1,  Roel Quintens 1
Affiliations

Affiliations

  • 1 Radiobiology Unit, Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), 2400 Mol, Belgium.
  • 2 Faculty of Bioscience Engineering, Ghent University, 9000 Ghent, Belgium.
  • 3 Laboratory for Computational Biology, Integromics and Gene Regulation (CBIGR), Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium.
  • 4 Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
  • 5 Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
  • 6 Laboratory for Neurophysiology, Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium.
  • 7 Laboratory of Cell Biology and Histology, Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, 2610 Wilrijk, Belgium.
PMID: 39967878 DOI: 10.1016/j.isci.2025.111853
Abstract

Prenatal radiation-induced DNA damage poses a significant threat to neurodevelopment, resulting in microcephaly which primarily affects the cerebral cortex. So far, mechanistic studies were done in rodents. Here, we leveraged human cortical organoids to model fetal corticogenesis. Organoids were X-irradiated with moderate or high doses at different time points. Irradiation caused a dose- and time-dependent reduction in Organoid size, which was more prominent in younger organoids. This coincided with a delayed and attenuated DNA damage response (DDR) in older organoids. Besides the DDR, radiation induced premature differentiation of neural progenitor cells (NPCs). Our transcriptomic analysis demonstrated a concerted p53-E2F4/DREAM-dependent repression of primary microcephaly genes, which was independently confirmed in cultured human NPCs and neurons. This was a human-specific feature, as it was not observed in mouse embryonic brains or primary NPCs. Thus, human cortical organoids are an excellent model for DNA damage-induced microcephaly and to uncover potentially targetable human-specific pathways.

Keywords

Developmental neuroscience; Neuroscience.

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