Abstract
Bcl-XL mice display a similar neurodevelopmental phenotype as rb, DNA ligase IV, and XRCC4 mutant embryos, suggesting that endogenous Bcl-XL expression may protect immature neurons from death caused by DNA damage and/or cell cycle dysregulation. To test this hypothesis, we generated bcl-x/p53 double mutants and examined neuronal cell death in vivo and in vitro. Bcl-XL-deficient primary telencephalic neuron cultures were highly susceptible to the apoptotic effects of cytosine arabinoside (AraC), a known genotoxic agent. In contrast, neurons lacking p53, or both Bcl-XL and p53, were markedly, and equivalently, resistant to AraC-induced caspase-3 activation and death in vitro indicating that Bcl-XL lies downstream of p53 in DNA damage-induced neuronal death. Despite the ability of p53 deficiency to protect Bcl-XL-deficient neurons from DNA damage-induced apoptosis in vitro, p53 deficiency had no effect on the increased caspase-3 activation and neuronal cell death observed in the developing Bcl-XL-deficient nervous system. These findings suggest that Bcl-XL expression in the developing nervous system critically regulates neuronal responsiveness to an apoptotic stimulus other than inadequate DNA repair or cell cycle abnormalities.
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Abbreviations
- AraC:
-
cytosine arabinoside
- DRG:
-
dorsal root ganglion
- H&E:
-
hematoxylin and eosin
- PBS-BB:
-
phosphate buffered saline-blocking buffer
- FCS:
-
fetal calf serum
- TSA:
-
tyramide signal amplification
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Acknowledgements
This work was supported by a grant from the National Institute of Health (NS35107). We thank A Schmeckebier for secretarial support and Dr. A Srinivasan (IDUN Pharmaceuticals) for the generous gift of CM1 antiserum.
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Klocke, B., Latham, C., D'Sa, C. et al. p53 deficiency fails to prevent increased programmed cell death in the Bcl-XL-deficient nervous system. Cell Death Differ 9, 1063–1068 (2002). https://doi.org/10.1038/sj.cdd.4401067
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DOI: https://doi.org/10.1038/sj.cdd.4401067
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