Y. Xu et al., TARGETED DISRUPTION OF ATM LEADS TO GROWTH-RETARDATION, CHROMOSOMAL FRAGMENTATION DURING MEIOSIS, IMMUNE DEFECTS, AND THYMIC LYMPHOMA, Genes & development, 10(19), 1996, pp. 2411-2422
ATM, the gene mutated in the inherited human disease ataxia-telangiect
asia, is a member of a family of kinases involved in DNA metabolism an
d cell-cycle checkpoint control. To help clarify the physiological rol
es of the ATM protein, we disrupted the ATM gene in mice through homol
ogous recombination, Initial evaluation of the ATM knockout animals in
dicates that inactivation of the mouse ATM gene recreates much of the
phenotype of ataxia-telangiectasia. The homozygous mutant (ATM(-/-)) m
ice are viable, growth-retarded, and infertile. The infertility of ATM
(-/-) mice results from meiotic failure. Meiosis is arrested at the zy
gotene/pachytene stage of prophase I as a result of abnormal chromosom
al synapsis and subsequent chromosome fragmentation. Immune defects al
so are evident in ATM(-/-) mice, including reduced numbers of B220(+)C
D43(-) pre-B cells, thymocytes, and peripheral T cells, as well as fun
ctional impairment of T-cell-dependent immune responses. The cerebella
of ATM(-/-) mice appear normal by histologic examination at 3 to 4 mo
nths and the mice have no gross behavioral abnormalities. The majority
of mutant mice rapidly develop thymic lymphomas and die before 4 mont
hs of age. These findings indicate that the ATM gene product plays an
essential role in a diverse group of cellular processes, including mei
osis, the normal growth of somatic tissues, immune development, and tu
mor suppression.