期刊
MUTAGENESIS
卷 28, 期 3, 页码 263-270出版社
OXFORD UNIV PRESS
DOI: 10.1093/mutage/ges080
关键词
-
资金
- National Institutes of Health/National Cancer Institute [R01CA123232, R01CA129537, R01CA154320, U19A1091175, R13CA130756, P01CA97403, R01CA137023]
Ataxia telangiectasia patients develop lymphoid malignancies of both B- and T-cell origin. Similarly, ataxia telangiectasia mutated (Atm)-deficient mice exhibit severe defects in T-cell maturation and eventually develop thymomas. The function of ATM is known to be influenced by the mammalian orthologue of the Drosophila MOF (males absent on the first) gene. Here, we report the effect of T-cell-specific ablation of the mouse Mof (Mof) gene on leucocyte trafficking and survival. Conditional Mof(Flox/Flox) (Mof(F/F)) mice expressing Cre recombinase under control of the T-cell-specific Lck proximal promoter (Mof(F/F)/Lck-Cre) display a marked reduction in thymus size compared with Mof(F/F)/Lck-Cre mice. In contrast, the spleen size of Mof(F/F)/Lck-Cre mice was increased compared with control Mof(F/F)/Lck-Cre mice. The thymus of Mof(F/F)/Lck-Cre mice contained significantly reduced T cells, whereas thymic B cells were elevated. Within the T-cell population, CD4CD8 double-positive T-cell levels were reduced, whereas the immature CD4CD8 double-negative (DN) population was elevated. Defective T-cell differentiation is also evident as an increased DN3 (CD44CD25) population, the cell stage during which T-cell receptor rearrangement takes place. The differentiation defect in T cells and reduced thymus size were not rescued in a p53-deficient background. Splenic B-cell distributions were similar between Mof(F/F)/Lck-Cre and Mof(F/F)/Lck-Cre mice except for an elevation of the light-chain population, suggestive of an abnormal clonal expansion. T cells from Mof(F/F)/Lck-Cre mice did not respond to phytohaemagglutinin (PHA) stimulation, whereas LPS-stimulated B cells from Mof(F/F)/Lck-Cre mice demonstrated spontaneous genomic instability. Mice with T-cell-specific loss of MOF had shorter lifespans and decreased survival following irradiation than did Mof(F/F)/Lck-Cre mice. These observations suggest that Mof plays a critical role in T-cell differentiation and that depletion of Mof in T cells reduces T-cell numbers and, by an undefined mechanism, induces genomic instability in B cells through bystander mechanism. As a result, these mice have a shorter lifespan and reduced survival after irradiation.
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