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Updated: Jun 13, 2026
Functional Interrogation of Adult Hypothalamic Neurogenesis with Focal Radiological Inhibition
Published on: November 14, 2013
A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in
Jessica Honorato Ribeiro1,2, Emre Etlioglu1, Jasmine Buset1
1Radiobiology Unit, Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), 2400 Mol, Belgium.
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.
Insights
Prenatal radiation exposure causes DNA damage and microcephaly, affecting brain development. Human cortical organoids reveal a human-specific pathway contributing to this condition.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Prenatal radiation exposure can cause DNA damage, leading to neurodevelopmental issues like microcephaly.
- Previous studies on radiation-induced microcephaly relied on rodent models, limiting human-specific insights.
- The cerebral cortex is particularly vulnerable to prenatal radiation damage.
Purpose of the Study:
- To model fetal corticogenesis and investigate the effects of radiation-induced DNA damage using human cortical organoids.
- To elucidate the mechanisms underlying radiation-induced microcephaly in a human context.
- To identify human-specific pathways involved in microcephaly pathogenesis.
Main Methods:
- X-irradiation of human cortical organoids at different doses and time points.
- Assessment of organoid size, DNA damage response (DDR), and neural progenitor cell (NPC) differentiation.
- Transcriptomic analysis to identify molecular pathways affected by radiation.
- Validation in cultured human NPCs and neurons, and comparison with mouse models.
Main Results:
- Irradiation caused dose- and time-dependent reductions in organoid size, more pronounced in younger organoids.
- A delayed and attenuated DNA damage response (DDR) was observed in older organoids.
- Radiation induced premature differentiation of NPCs and a human-specific p53-E2F4/DREAM-dependent repression of microcephaly genes.
Conclusions:
- Human cortical organoids serve as a robust model for studying DNA damage-induced microcephaly.
- Radiation impacts neurodevelopment through premature NPC differentiation and a unique human-specific gene regulation pathway.
- This study uncovers potentially targetable, human-specific pathways for treating radiation-induced microcephaly.
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