Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice

Motor incoordination. immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia-telangiect asia (A-T), which is caused by mutations in the ATM gene, Through gene targ eting, we have generated a line of Atm mutant mice, Atm(y/y) mice. In contr ast to other Atm mutant mice, Atm(y/y) mice show a lower incidence of thymi c lymphoma and survive beyond a few months of age. Atm(y/y) mice exhibit de ficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atm(y/y) animals, ectopi c and abnormally differentiated Purkinje cells were apparent in mutant mice of ail ages. These findings establish that some neuropathological abnormal ities seen in A-T patients also are present in Atm mutant mice. In addition , we report a previously unrecognized effect of Atm deficiency on developme nt or maintenance of CD4(+)8(+) thymocytes. We discuss these findings in th e context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T.