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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
Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse
Mirella Tanori1, Emanuela Pasquali, Simona Leonardi
1Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy.
Abstract:
Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1(+/-)) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1(+/-) mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and fate-restricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors.
Insights
Neural stem cells (NSCs) and progenitor cells (PCs) show distinct DNA damage responses and oncogenic vulnerability. Radiation exposure timing significantly impacts DNA repair and tumor development in a mouse model of medulloblastoma.
Area of Science:
- Neuroscience
- Developmental Biology
- Radiation Oncology
Background:
- Neural stem cells (NSCs) and progenitor cells (PCs) are vulnerable to DNA damage, but their response mechanisms and long-term effects of genotoxic exposure remain unclear.
- Medulloblastoma (MB), a pediatric brain tumor, is frequently modeled using Patched1 heterozygous (Ptc1(+/-)) mice, where irradiation accelerates MB development.
Purpose of the Study:
- To investigate how cerebellar NSCs and PCs respond to radiation-induced DNA damage.
- To determine the long-term developmental and oncogenic consequences of this damage at different embryonic stages.
- To elucidate the differentiation-stage specificity of DNA repair pathways in neural development.
Main Methods:
- Utilized Ptc1(+/-) mice irradiated at embryonic day 13.5 or 16.5 with low (0.25 Gy) or high (3 Gy) doses.
- Assessed DNA damage response (DDR), apoptosis, and oncogenic alterations in NSCs and fate-restricted PCs.
- Compared responses based on cell type, radiation dose, and developmental stage at exposure.
Main Results:
- Observed significant differences in DDR and apoptosis between NSCs and PCs, notably absent p21 expression in NSCs.
- Found NSCs resistant to low-dose radiation oncogenesis but vulnerable at higher doses.
- Demonstrated that DNA repair pathways and oncogenic alterations are highly dependent on the age of exposure, indicating stage-specific responses.
Conclusions:
- NSCs and PCs exhibit distinct mechanisms for maintaining genome integrity during neurogenesis.
- Findings highlight the critical role of developmental stage in determining cellular response to radiation.
- Results have implications for radiation risk assessment and targeted therapies for brain tumors like medulloblastoma.
