T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice

Arun Gupta, Clayton R. Hunt, Raj K. Pandita, Juhee Pae, K. Komal, Mayank Singh, Jerry W. Shay, Rakesh Kumar, Kiyoshi Ariizumi, Nobuo Horikoshi, Walter N. Hittelman, Chandan Guha, Thomas Ludwig, Tej K. Pandita

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27 Scopus citations

Abstract

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 MofFlox/Flox (MofF/F) mice expressing Cre recombinase under control of the T-cell-specific Lck proximal promoter (MofF/F/Lck-Cre+) display a marked reduction in thymus size compared with MofF/F/Lck-Cre- mice. In contrast, the spleen size of MofF/F/Lck-Cre+ mice was increased compared with control MofF/F/Lck-Cre- mice. The thymus of MofF/F/Lck-Cre+ mice contained significantly reduced T cells, whereas thymic B cells were elevated. Within the T-cell population, CD4+CD8+ double-positive T-cell levels were reduced, whereas the immature CD4-CD8- double-negative (DN) population was elevated. Defective T-cell differentiation is also evident as an increased DN3 (CD44-CD25+) 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 MofF/F/Lck-Cre+ and Mof F/F/Lck-Cre- mice except for an elevation of the κ light-chain population, suggestive of an abnormal clonal expansion. T cells from MofF/F/Lck-Cre+ mice did not respond to phytohaemagglutinin (PHA) stimulation, whereas LPS-stimulated B cells from MofF/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 MofF/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.

Original languageEnglish (US)
Pages (from-to)263-270
Number of pages8
JournalMutagenesis
Volume28
Issue number3
DOIs
StatePublished - May 2013

ASJC Scopus subject areas

  • Genetics
  • Toxicology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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    Gupta, A., Hunt, C. R., Pandita, R. K., Pae, J., Komal, K., Singh, M., Shay, J. W., Kumar, R., Ariizumi, K., Horikoshi, N., Hittelman, W. N., Guha, C., Ludwig, T., & Pandita, T. K. (2013). T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice. Mutagenesis, 28(3), 263-270. https://doi.org/10.1093/mutage/ges080