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Journal of Neuroscience, Vol 15, 5851-5857, Copyright © 1995 by Society for Neuroscience
The role of free radicals and p53 in neuron apoptosis in vivo
KA Wood and RJ Youle
Biochemistry Section, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
Apoptosis is a mechanism of cell death operative in the normal development
and regulation of vertebrate tissues and organ cellularity. During the
postnatal development of the mouse cerebellum, extensive granule neuron
apoptosis occurs that may regulate the final granule cell to Purkinje cell
stoichiometry observed in the adult. Cerebellar granule cells are highly
sensitive to genotoxic agents such as gamma- irradiation and
methylazoxymethanol during the first 2 weeks of postnatal development. We
demonstrate that ionizing radiation induces extensive cerebellar granule
cell death via apoptosis in vivo. In p53 null mice, however, the cerebellar
granule cells do not undergo apoptosis in response to gamma-irradiation. In
mice heterozygous for the p53 allele, the granule cells apoptosis is
delayed, indicating an intermediate response. The developmental apoptosis
of cerebellar granule cells, however, occurs similarly in wild-type and p53
null mice. Therefore, neurons undergo p53-dependent and p53-independent
apoptosis, depending upon the initiating stimulus that triggers DNA
fragmentation. In contrast to x-ray damage, the extensive death of
cerebellar granule cells induced by methylazoxymethanol was found to be
independent of the DNA fragmentation characteristic of apoptosis, and was
also independent of expression of p53. Ablation of neuron progenitor cells
with genotoxic agents may occur by p53-dependent apoptosis or by
p53-independent mechanisms not associated with DNA fragmentation.
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