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Updated: Jun 13, 2025
Assessing Cell Cycle Progression of Neural Stem and Progenitor Cells in the Mouse Developing Brain after Genotoxic Stress
Published on: May 7, 2014
Interneuron migration impairment and brain region-specific DNA damage response following irradiation during early
Lisa Berden1,2, Nicholas Rajan1, André Claude Mbouombouo Mfossa1
1Radiobiology Unit, Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium.
Abstract:
Embryonic DNA damage resulting from DNA repair deficiencies or exposure to ionizing radiation during early neurogenesis can lead to neurodevelopmental disorders, including microcephaly. This has been linked to an excessive DNA damage response in dorsal neural progenitor cells (NPCs), resulting in p53-dependent apoptosis and premature neuronal differentiation which culminates in depletion of the NPC pool. However, the effect of DNA damage on ventral forebrain NPCs, the origin of interneurons, remains unclear. In this study, we investigated the sequelae of irradiation of mouse fetuses at an early timepoint of forebrain neurogenesis. We focused on the neocortex (NCX) and medial ganglionic eminence (MGE), key regions for developing dorsal and ventral NPCs, respectively. Although both regions showed a typical p53-mediated DNA damage response consisting of cell cycle arrest, DNA repair and apoptosis, NCX cells displayed prolonged cell cycle arrest, while MGE cells exhibited more sustained apoptosis. Moreover, irradiation reduced the migration speed of interneurons in acute living brain slices and MGE explants, the latter indicating a cell-intrinsic component in the defect. RNA sequencing and protein analyses revealed disruptions in actin and microtubule cytoskeletal-related cellular machinery, particularly in MGE cells. Despite massive acute apoptosis and an obvious interneuron migration defect, prenatally irradiated animals did not show increased sensitivity to pentylenetetrazole-induced seizures, nor was there a reduction in cortical interneurons in young adult mice. This suggests a high plasticity of the developing brain to acute insults during early neurogenesis. Overall, our findings indicate that embryonic DNA damage induces region-specific responses, potentially linked to neurodevelopmental disorders.
Insights
Embryonic DNA damage affects developing brain cells differently depending on their region. While ventral forebrain cells show more apoptosis, the brain
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Embryonic DNA damage can cause neurodevelopmental disorders like microcephaly.
- Excessive DNA damage response in dorsal neural progenitor cells (NPCs) leads to apoptosis and premature differentiation, depleting the NPC pool.
- The impact of DNA damage on ventral forebrain NPCs, crucial for interneuron development, is not well understood.
Purpose of the Study:
- Investigate the effects of embryonic DNA damage on dorsal (neocortex) and ventral (medial ganglionic eminence) forebrain NPCs.
- Analyze region-specific responses to DNA damage during early neurogenesis.
- Determine the long-term consequences of prenatal irradiation on brain development and function.
Main Methods:
- Irradiation of mouse fetuses during early forebrain neurogenesis.
- Analysis of DNA damage response, cell cycle, apoptosis, and cell migration in neocortex and medial ganglionic eminence.
- RNA sequencing and protein analysis to identify molecular mechanisms.
- Assessment of seizure susceptibility and interneuron numbers in young adult mice.
Main Results:
- Both neocortex and medial ganglionic eminence NPCs exhibited p53-mediated DNA damage response.
- Neocortex cells showed prolonged cell cycle arrest, while medial ganglionic eminence cells displayed more sustained apoptosis.
- Irradiation reduced interneuron migration speed, indicating a cell-intrinsic defect.
- Disruptions in cytoskeletal machinery (actin, microtubules) were observed, particularly in medial ganglionic eminence cells.
Conclusions:
- Embryonic DNA damage induces region-specific responses in neural progenitor cells.
- Prenatal irradiation leads to interneuron migration defects but does not cause long-term deficits in seizure susceptibility or interneuron numbers.
- The developing brain exhibits significant plasticity in response to acute insults during early neurogenesis.
- These region-specific responses may contribute to the etiology of neurodevelopmental disorders.
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