The tumour suppressor p53 gene serves as a critical regulator of the cell cycle and of apoptosis following the exposure of normal cells to DNA damage. To examine the role of p53 in postmitotic CNS neurons, we cultured cerebellar neurons from normal wild-type mice and mutant p53-null mice under various conditions inducing neuronal death. When cerebellar neurons from 15- to 16-day postnatal wild-type mice were treated with ionizing radiation or DNA-damaging agents, massive neuron death occurred after 24-72 h. In contrast, neurons from p53-/- mice evidently resisted gamma-irradiation and some DNA-damaging agents, such as etoposide and bleomycin. On the other hand, low-K+ medium-induced apoptosis of cerebellar neurons was not affected by p53 status. Neither cell cycle progression nor DNA synthesis occurred during cell death induced by gamma-irradiation and low-K+ medium, as well as in normal cultures of p53+/+ and p53-/- neurons. These results suggest that p53 is required for the apoptotic death of postmitotic cerebellar neurons induced by DNA strand breaks.