The tumor-suppressor protein p53 has been implicated in cell cycle arrest and apoptotic cell death in dividing cells (Yonish-Rouach et al. [1991] Nature 352:342-347. To elucidate possible functions of p53 in the regulation of cell division and cell death during development of the rat central nervous system, we compared the spatial and temporal expressions of p53 mRNA and protein with those of its transcriptional targets Bax, p21Waf1, and cyclin G1 and with the cyclin-dependent kinase inhibitors p27Kip1, p57Kip2, and p16Ink4a. From embryonic day 14 until the second postnatal week, p53 mRNA and protein were found predominantly in proliferating zones, including the cells of the emerging external granular layer of the cerebellum, and the ventricular and the subventricular zones of the forebrain. At all postnatal ages, there was a high expression of p53 mRNA and protein in cells of the rostral migratory stream, a well-defined pathway along which precursor cells of olfactory interneurons migrate from the ventricular and subventricular zones toward the olfactory bulb. In addition to its expression in proliferating cell populations, p53 was expressed in postmitotic cells of the cerebral cortex and hippocampus at embryonic and early postnatal stages. p53, p27Kip1, p16Ink4a, and bax alpha mRNA colocalized in the ventricular and subventricular zones at embryonic and early postnatal stages, but the distribution of p53 differed from that of its transcriptional targets cyclin G1 and p21Waf1 and from that of the cyclin-dependent kinase inhibitor p57Kip2, which were predominantly expressed in fully differentiated neurons. Double-labeling studies showed that p53 mRNA and protein were absent in cells undergoing developmental cell death, as identified by the presence of single- or double-stranded nuclear DNA breaks. Protein levels of p53 decreased during development in all brain areas studied. These results indicate a role for p53 in the control of cell division and early differentiation rather than in the control of cell death during rat brain development. The nonoverlapping temporal and spatial expression patterns of p53 and its transcriptional targets Bax, cyclin G1 and p21Waf1 suggest that each of these gene products fulfill independent roles in brain morphogenesis.