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

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 wa

SUBMITTER: Ribeiro JH 

PROVIDER: S-EPMC11834077 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature