title: Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma.
abstract: ATM, the gene mutated in the inherited human disease ataxia-telangiectasia, is a member of a family of kinases involved in DNA metabolism and cell-cycle checkpoint control. To help clarify the physiological roles of the ATM protein, we disrupted the ATM gene in mice through homologous recombination. Initial evaluation of the ATM knockout animals indicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia. The homozygous mutant (ATM-/-) mice are viable, growth-retarded, and infertile. The infertility of ATM-/- mice results from meiotic failure. Meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. Immune defects also are evident in ATM-/- mice, including reduced numbers of B220+CD43- pre-B cells, thymocytes, and peripheral T cells, as well as functional impairment of T-cell-dependent immune responses. The cerebella of ATM-/- mice appear normal by histologic examination at 3 to 4 months and the mice have no gross behavioral abnormalities. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age. These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including meiosis, the normal growth of somatic tissues, immune development, and tumor suppression.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: T
authors.initials: T
authors.lastname: Ashley
authors.forename: E E
authors.initials: EE
authors.lastname: Brainerd
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: M S
authors.initials: MS
authors.lastname: Meyn
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000166:cytology; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000097:blood; D007246:Infertility; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000254:growth & development; D008223:Lymphoma / Q000209:etiology*; D008297:Male; D008540:Meiosis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010053:Ovary / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012671:Seminiferous Tubules / Q000473:pathology; D013091:Spermatogenesis / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D013953:Thymus Neoplasms / Q000209:etiology*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases