Differential post-transcriptional regulation of p21WAF1/Cip1 levels in the developing nervous system following gamma-irradiation.

Abstract

Radiation-induced death in the developing brain is p53-dependent. However, genetic studies indicate that the signalling pathways that couple irradiation to p53 expression can vary between different developing neural populations [Herzog et al. (1998) Science, 280, 1089-1091]. Here we establish that signalling downstream of p53 also exhibits brain region-specific differences that are associated with the relative vulnerability of some cell populations to radiation-induced killing in the mouse. Following gamma-irradiation, p53 and p21WAF1/cip1, but not Bax, protein levels increased in the developing cerebellum. In contrast, neither p21WAF1/cip1 nor Bax protein levels were elevated in the retina following irradiation, despite increased p53 expression. In the retina, p53 expression was associated with cells destined to die, whereas in the cerebellum, p53 was expressed in both radiation-sensitive and radiation-resistant neuroblasts of the external granule cell layer. Although p21WAF1/cip1 mRNA was expressed in all p53-positive neuroblasts after irradiation, p21WAF1/cip1 protein was only detected in radiation-resistant neuroblasts of the cerebellum. Thus, p21WAF1/cip1 was subject to post-transcriptional regulation with p21WAF1/cip1 protein only accumulating in cells destined to survive irradiation. Nevertheless, p21WAF1/cip1 function was not essential for radiation resistance, as postmitotic neuroblasts in the external granule cell layer were spared in p21WAF1/cip1 knockout mice.