The p53 tumor suppressor gene, which is considered the guardian of the genome, encodes a phosphoprotein, which is a sequence-specific transcriptional activator or repressor of target genes. The role of p53 in developmental processes has not been studied extensively, although its expression appears to undergo temporal and spatial changes during prenatal and postnatal development. In the present study, we assessed the levels of p53 mRNA and protein in the developing rat brain and its relation to developmental cell death. Furthermore, we investigated the potential role of n-methyl-d-aspartate (NMDA) receptors in regulating p53 expression, since these receptors are involved in the control of cell death. We found that p53 mRNA and protein were detectable in the rat brain throughout perinatal development. In embryos, p53 immunoreactivity was mainly localized in the nuclei of neuroepithelial cells, with a maximum in staining at embryonic day (E)12. In the neuroepithelium, we also found significant numbers of TdT-mediated dUTP nick end labeling (TUNEL)-positive cells, both in dividing periventricular cells and in migrating neurons. In neonates, immediately after birth there was a reduction in the number of apoptotic cells, which then increased to reach a maximum at postnatal day (P)5. Postnatally, apoptotic as well as p53-positive cells were detected in most brain areas. P53 immunoreactivity was also highest on P5. In most cells, p53 immunoreactivity and the TUNEL signal colocalized. P53 immunoreactivity as well as the number of TUNEL- positive cells were dramatically decreased in the brains of newborns treated with MK-801, an NMDA receptor antagonist. Our results show that p53 is involved in the control of developmental cell death, and that NMDA receptors play a regulatory role in the expression of the p53 gene, and thus in apoptosis occurring in the developing rat brain.