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We tested the hypothesis that p53 and Bax regulate this neuronal apoptosis, and that DNA damage is an early upstream signal. Adult mice and rats received unilateral avulsions causing lumbar motor neurons to achieve endstage apoptosis at 7\u201314 days postlesion. This motor neuron apoptosis is blocked in <jats:italic>bax<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and <jats:italic>p53<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Single\u2010cell gel electrophoresis (comet assay), immunocytochemistry, and quantitative immunogold electron microscopy were used to measure molecular changes in motor neurons during the progression of apoptosis. Injured motor neurons accumulate single\u2010strand breaks in DNA by 5 days. p53 accumulates in nuclei of motor neurons destined to undergo apoptosis. p53 is functionally activated by 4\u20135 days postlesion, as revealed by immunodetection of phosphorylated p53. Preapoptotically, Bax translocates to mitochondria, cytochrome <jats:italic>c<\/jats:italic> accumulates in the cytoplasm, and caspase\u20103 is activated. These results demonstrate that motor neuron apoptosis in the adult spinal cord is controlled by upstream mechanisms involving DNA damage and activation of p53 and downstream mechanisms involving upregulated Bax and cytochrome <jats:italic>c<\/jats:italic> and their translocation, accumulation of mitochondria, and activation of caspase\u20103. We conclude that adult motor neuron death after nerve avulsion is DNA damage\u2010induced, p53\u2010 and Bax\u2010dependent apoptosis. \u00a9 2002 Wiley Periodicals, Inc. 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