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Assessing Cell Cycle Progression of Neural Stem and Progenitor Cells in the Mouse Developing Brain after Genotoxic Stress
Published on: May 7, 2014
Confined migration induces non-lethal DNA damage in developing neurons
Zhejing Zhang1,2, Andres Canela2,3, Junko Kurisu1
1Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Kyoto, Japan.
Abstract:
Migratory cells tend to have soft nuclei that deform and penetrate narrow spaces1,2. Extensive nuclear deformation during migration can cause nuclear-envelope rupture and DNA damage in cancer cells, which may contribute to malignant transformation during tumour progression3-6. However, the importance of DNA damage in physiological migration is less well understood. Here we demonstrate that the migration of neurons in developing cerebral and cerebellar cortices is accompanied by massive DNA double-stranded breaks (DSBs) due to mechanostress during passage through narrow interstitial spaces. In contrast to many other migratory cells, these DSBs occur without detectable nuclear envelope rupture. Confined migration increases topoisomerase-IIβ covalently bound DSBs, and these lesions are repaired through non-homologous end-joining during brain development without causing cell death. Genome sequencing revealed that DSBs tend to occur at transcriptionally inactive regions. The deletion of ligase IV at the onset of neuronal migration leads to persistent DSB accumulation in cerebellar neurons with moderate transcriptional changes in genes related to synaptic function, neuronal development and stress and immune responses. The mutant mouse develops mild motor deficits in later life, suggesting that the DNA damage generated during normal brain development poses a potential disease risk if left unrepaired.
Insights
During brain development, migrating neurons experience DNA double-stranded breaks (DSBs) from physical stress. These breaks are repaired without cell death, but unrepaired damage may pose future disease risks.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Migratory cells, including cancer cells, can experience nuclear deformation and DNA damage during migration through confined spaces.
- The role and consequences of DNA damage during physiological cell migration, particularly in the developing brain, remain less understood.
Purpose of the Study:
- To investigate the occurrence and mechanisms of DNA damage in migrating neurons during brain development.
- To understand the cellular response and long-term implications of DNA damage in developing neurons.
Main Methods:
- Utilized mouse models of brain development.
- Analyzed DNA double-stranded breaks (DSBs) using molecular assays.
- Performed genome sequencing to identify DSB locations.
- Investigated the role of specific genes (e.g., ligase IV) in DNA repair during neuronal migration.
Main Results:
- Neuronal migration in the developing cortex is associated with massive DNA double-stranded breaks (DSBs) caused by mechanical stress in narrow spaces.
- These DSBs occur without nuclear envelope rupture and are repaired via non-homologous end-joining, with no observed cell death.
- DSBs preferentially occur in transcriptionally inactive genomic regions.
- Deletion of ligase IV leads to persistent DSBs and mild motor deficits in adult mice, indicating potential disease risk.
Conclusions:
- Mechanical stress during neuronal migration in the developing brain induces significant DNA double-stranded breaks.
- Efficient DNA repair mechanisms are crucial for preventing long-term consequences of developmental DNA damage.
- Failure to repair these endogenous DNA breaks may contribute to neurological disorders later in life.
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