title: T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice.
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 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, 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 Mof(F/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 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.
authors: Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75229, USA.
authors: Arun
authors: A
authors: Gupta
authors: Clayton R
authors: CR
authors: Hunt
authors: Raj K
authors: RK
authors: Pandita
authors: Juhee
authors: J
authors: Pae
authors: K
authors: K
authors: Komal
authors: Mayank
authors: M
authors: Singh
authors: Jerry W
authors: JW
authors: Shay
authors: Rakesh
authors: R
authors: Kumar
authors: Kiyoshi
authors: K
authors: Ariizumi
authors: Nobuo
authors: N
authors: Horikoshi
authors: Walter N
authors: WN
authors: Hittelman
authors: Chandan
authors: C
authors: Guha
authors: Thomas
authors: T
authors: Ludwig
authors: Tej K
authors: TK
authors: Pandita
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D017353:Gene Deletion; D042822:Genomic Instability; D051548:Histone Acetyltransferases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective; D009929:Organ Size; D011836:Radiation Tolerance / Q000235:genetics; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; C000622683:Kat8 protein, mouse
references: Mol Cell Biol. 2006 Mar;26(5):1850-64
references: 16479004
references: Nucleic Acids Res. 2009 Apr;37(5):1363-77
references: 19139074
references: Mol Cell Biol. 2005 Jun;25(12):5292-305
references: 15923642
references: Int J Radiat Biol. 1994 Dec;66(6 Suppl):S23-9
references: 7836849
references: Int J Radiat Biol. 2010 Feb;86(2):102-13
references: 20148696
references: Mutat Res. 1986 Aug-Sep;171(2-3):131-8
references: 3528835
references: Cancer Res. 1996 Sep 15;56(18):4130-3
references: 8797579
references: Cytogenet Cell Genet. 1995;71(1):86-93
references: 7606935
references: J Exp Med. 1982 Mar 1;155(3):914-23
references: 6977612
references: Mutat Res. 2002 Jul 25;504(1-2):91-100
references: 12106650
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3636-41
references: 21321203
references: Mol Cell Biol. 2005 Aug;25(15):6798-810
references: 16024812
references: Cell Cycle. 2006 Jun;5(12):1289-91
references: 16760671
references: Microbiol Mol Biol Rev. 2000 Jun;64(2):435-59
references: 10839822
references: Nat Genet. 1996 Sep;14(1):33-41
references: 8782817
references: Mol Cell Biol. 2003 Nov;23(22):8363-76
references: 14585993
references: Blood. 2000 Sep 1;96(5):1940-6
references: 10961898
references: Oncogene. 2002 Jan 21;21(4):611-8
references: 11850786
references: Cancer Res. 2003 Jan 15;63(2):324-8
references: 12543783
references: Eur J Hum Genet. 1995;3(2):116-38
references: 7552141
references: EMBO J. 1997 Apr 15;16(8):2054-60
references: 9155031
references: Hum Genet. 1983;63(2):189-90
references: 6840763
references: Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1394-7
references: 1996340
references: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6323-8
references: 17405860
references: Cancer Res. 1995 Dec 15;55(24):5991-6001
references: 8521380
references: Chromosoma. 2012 Feb;121(1):79-90
references: 22072291
references: Immunol Rev. 1988 Feb;102:5-28
references: 2966762
references: Expert Rev Mol Med. 2003 Jun 20;5(16):1-21
references: 14987398
references: Science. 1994 Jul 1;265(5168):103-6
references: 8016642
references: Mol Cell Biol. 2004 Jan;24(2):899-911
references: 14701760
references: Immunology. 2000 Aug;100(4):417-23
references: 10929067
references: Eukaryot Cell. 2005 Dec;4(12):2057-65
references: 16339723
references: Science. 2006 Feb 10;311(5762):844-7
references: 16469925
references: Nat Genet. 2002 Nov;32(3):378-83
references: 12379856
references: Mutat Res. 1988 Apr;204(4):627-43
references: 3280996
references: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13084-9
references: 8917548
references: Mol Cell Biol. 2010 Jul;30(14):3582-95
references: 20479123
references: Blood. 2009 May 14;113(20):4866-74
references: 19264921
references: Mol Cell Biol. 2008 Jan;28(1):397-409
references: 17967868