p53 deficiency fails to prevent increased programmed cell death in the Bcl-XL-deficient nervous system

BcI-X-L mice display a similar neurodevelopmental phenotype as rb, DNA ligase IV, and XRCC4 mutant embryos, suggesting that endogenous BCI-X-L expression may protect immature neurons from death caused by DNA damage and/or cell cycle dysregulation. To test this hypothesis, we generated bcI-x/p53 double mutants and examined neuronal cell death in vivo and in vitro. BCI-X-L-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 BCI-X-L and p53, were markedly, and equivalently, resistant to AraC-induced caspase-3 activation and death in vitro indicating that BCI-X-L lies downstream of p53 in DNA damage-induced neuronal death. Despite the ability of p53 deficiency to protect BCI-X-L-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 BCI-X-L-deficient nervous system. These findings suggest that Bcl-X-L expression in the developing nervous system critically regulates neuronal responsiveness to an apoptotic stimulus other than inadequate DNA repair or cell cycle abnormalities.