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 A TM-/-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.

Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort

“…Indeed, there is increasing evidence that growth failure in AT is caused directly by the impairment in ATM gene function. Growth failure is a prominent prenatal and postnatal feature of mutant atm -/-mice (23,24). Accordingly, human AT fibroblast lines, as well as fibroblasts from the atm -/-mice, grow slowly, undergo premature senescence, and have high requirements for growth factors (17,(23)(24)(25).…”

“…Growth failure is a prominent prenatal and postnatal feature of mutant atm -/-mice (23,24). Accordingly, human AT fibroblast lines, as well as fibroblasts from the atm -/-mice, grow slowly, undergo premature senescence, and have high requirements for growth factors (17,(23)(24)(25). Impaired IGF-I activity may be implicated, as fibroblasts obtained from AT-affected individuals show low levels of IGF-I receptor (IGF-IR) expression and decreased IGF-IR promoter activity (26).…”

“…The uterine lining does not show evidence of proliferation or degeneration, and there is no estrous cycling (24). This may be attributed to Atm control of the number of meiotic double-strand-break (DSB) created by Spo11, important for meiotic recombination during gametogenesis in spermatogonia and priomordial follicle (23,24,30). This mechanism may partially explain the finding of sexual dimorphism: in males, disruption of meiosis would be expected to affect mainly spermatogenesis, while testosterone production by Leydig cells would not be affected.…”

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

“…Previous studies on AtmÀ/À MEFs have indicated a significant involvement of p53 and p21 in cellular defects dependent on the absence of ATM (Xu et al, 1996(Xu et al, , 1998. In fact, following DNA damage, ATM phosphorylates p53 and enhances its transcriptional activity on several target promoters, such as p21 (Lavin and Kozlov 2007).…”

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…(Barlow et al,1996;Ch'ang et al, 2005;Peter et al, 2001) Immunodeficieny. (Elson et al,2001;Xu et al, 1996 ;Bagley et al, 2004) Osteoporosis. (Rasheed et al, 2006;Hishiya et al,2005) Shortened lifespan due to premature aging.…”