Related Experiment Videos
DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3
C D'Sa-Eipper1, J R Leonard, G Putcha
1Department of Pathology, Division of Neuropathology, Washington University School of Medicine, St Louis, MO 63110, USA.
Abstract:
Programmed cell death (apoptosis) is critical for normal brain morphogenesis and may be triggered by neurotrophic factor deprivation or irreparable DNA damage. Members of the Bcl2 and caspase families regulate neuronal responsiveness to trophic factor withdrawal; however, their involvement in DNA damage-induced neuronal apoptosis is less clear. To define the molecular pathway regulating DNA damage-induced neural precursor cell apoptosis, we have examined the effects of drug and gamma-irradiation-induced DNA damage on telencephalic neural precursor cells derived from wild-type embryos and mice with targeted disruptions of apoptosis-associated genes. We found that DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9, but neither Bax nor caspase 3 expression. Neural precursor cell apoptosis was also unaffected by targeted disruptions of Bclx and Bcl2, and unlike neurotrophic factor-deprivation-induced neuronal apoptosis, was not associated with a detectable loss of cytochrome c from mitochondria. The apoptotic pathway regulating DNA damage-induced neural precursor cell death is different from that required for normal brain morphogenesis, which involves both caspase 9 and caspase 3 but not p53, indicating that additional apoptotic stimuli regulate neural precursor cell numbers during telencephalic development.
Insights
DNA damage triggers programmed cell death (apoptosis) in neural precursor cells via p53 and caspase 9. This pathway differs from normal brain development, highlighting distinct apoptosis regulators.
Area of Science:
- Neuroscience
- Developmental Biology
- Cellular Biology
Background:
- Programmed cell death (apoptosis) is crucial for brain development.
- The roles of Bcl2 and caspase families in DNA damage-induced neuronal apoptosis are not fully understood.
- Understanding these pathways is vital for comprehending neural precursor cell regulation.
Purpose of the Study:
- To elucidate the molecular mechanisms of DNA damage-induced apoptosis in telencephalic neural precursor cells.
- To investigate the involvement of p53, Bax, Bcl2 family members, and caspases in this process.
- To compare the apoptotic pathways triggered by DNA damage versus neurotrophic factor deprivation.
Main Methods:
- Utilized drug and gamma-irradiation to induce DNA damage in neural precursor cells from wild-type and genetically modified mice.
- Examined apoptosis in vitro and in vivo.
- Assessed the expression and function of key apoptosis-related genes, including p53, Bax, Bclx, Bcl2, and caspases (3 and 9).
- Monitored cytochrome c release from mitochondria.
Main Results:
- DNA damage-induced neural precursor cell apoptosis is dependent on p53 and caspase 9.
- Bax and caspase 3 expression were not essential for this apoptotic pathway.
- Disruptions in Bclx and Bcl2 did not affect DNA damage-induced apoptosis.
- Unlike apoptosis from trophic factor withdrawal, this process did not involve detectable cytochrome c release.
Conclusions:
- The apoptotic pathway activated by DNA damage in neural precursor cells relies on p53 and caspase 9.
- This pathway is distinct from the one involved in normal brain morphogenesis, which requires caspase 3 and p53-independently.
- Additional apoptotic stimuli likely regulate neural precursor cell numbers during development.