MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome

被引:27
作者
Assaf, Yaniv [1 ,2 ]
Galron, Ronit [2 ]
Shapira, Ital [2 ]
Nitzan, Anat [2 ]
Blumenfeld-Katzir, Tamar [2 ]
Solomon, Arieh S. [3 ]
Holdengreber, Vered [4 ]
Wang, Zhao-Qi [5 ,6 ]
Shiloh, Yosef [7 ]
Barzilai, Ari [2 ]
机构
[1] Tel Aviv Univ, Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel
[2] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel
[3] Chaim Sheba Med Ctr, Goldschleger Eye Res Inst, IL-52621 Tel Hashomer, Israel
[4] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel
[5] Fritz Lipmann Inst, Leibniz Inst Age Res, D-07745 Jena, Germany
[6] Univ Jena, D-07745 Jena, Germany
[7] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, David & Inez Myers Lab Genet Res, IL-69978 Tel Aviv, Israel
基金
以色列科学基金会;
关键词
NBS; Nbsl conditional knockout; MRI; white matter; myelin; oligodentrocytes;
D O I
10.1016/j.expneurol.2007.09.021
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBSI gene encoding the NbsI (nibrin) protein. Nbs I is a component of the Mrel 1/Rad50/NbsI (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of NBS1, Nbn, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. In this study we used MRI to study the brain morphology and organization of Nbn deleted mice. Using conventional T-2-weighted magnetic resonance, we found that the brains of the mutant mice (NbsI -CNS-del) were significantly smaller than those of the wild-type animals, with marked mal-development of the cerebellum. Region of interest analysis of the T2 maps revealed significant T2 increase in the areas of white matter (corpus callosum, internal capsule and midbrain), with minor changes, if any, in gray matter. Diffusion tensor imaging (DTI) data confirmed that fractional anisotropy values were significantly reduced in these areas, mainly due to increased radial diffusivity (water diffusion perpendicular to neuronal fibers). Biochemical analysis showed low and dispersed staining for MBP and GaIC in Nbs I -CNS-del brains, indicating defects in myelin fort-nation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of NbsI in the development and organization of the white matter. (c) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:181 / 191
页数:11
相关论文
共 54 条
  • [1] DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
    Bakkenist, CJ
    Kastan, MB
    [J]. NATURE, 2003, 421 (6922) : 499 - 506
  • [2] Atm-deficient mice: A paradigm of ataxia telangiectasia
    Barlow, C
    Hirotsune, S
    Paylor, R
    Liyanage, M
    Eckhaus, M
    Collins, F
    Shiloh, Y
    Crawley, JN
    Ried, T
    Tagle, D
    WynshawBoris, A
    [J]. CELL, 1996, 86 (01) : 159 - 171
  • [3] A simplified method to measure the diffusion tensor from seven MR images
    Basser, PJ
    Pierpaoli, C
    [J]. MAGNETIC RESONANCE IN MEDICINE, 1998, 39 (06) : 928 - 934
  • [4] Bekiesinska-Figatowska M, 2004, ACTA NEUROBIOL EXP, V64, P503, DOI 10.55782/ane-2004-1532
  • [5] Cranial MRI in the Nijmegen breakage syndrome
    Bekiesinska-Figatowska, M
    Chrzanowska, KH
    Sikorska, J
    Walecki, J
    Krajewska-Walasek, M
    Józwiak, S
    Kleijer, WJ
    [J]. NEURORADIOLOGY, 2000, 42 (01) : 43 - 47
  • [6] The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: Linkage of double-strand break repair to the cellular DNA damage response
    Carney, JP
    Maser, RS
    Olivares, H
    Davis, EM
    Le Beau, M
    Yates, JR
    Hays, L
    Morgan, WF
    Petrini, JHJ
    [J]. CELL, 1998, 93 (03) : 477 - 486
  • [7] Independent roles for nibrin and Mre11-Rad50 in the activation and function of Atm
    Cerosaletti, K
    Concannon, P
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) : 38813 - 38819
  • [8] 11 POLISH PATIENTS WITH MICROCEPHALY, IMMUNODEFICIENCY, AND CHROMOSOMAL INSTABILITY - THE NIJMEGEN BREAKAGE SYNDROME
    CHRZANOWSKA, KH
    KLEIJER, WJ
    KRAJEWSKAWALASEK, M
    BIALECKA, M
    GUTKOWSKA, A
    GORYLUKKOZAKIEWICZ, B
    MICHALKIEWICZ, J
    STACHOWSKI, J
    GREGOREK, H
    LYSONWOJCIECHOWSKA, G
    JANOWICZ, W
    JOZWIAK, S
    [J]. AMERICAN JOURNAL OF MEDICAL GENETICS, 1995, 57 (03): : 462 - 471
  • [9] Ataxia-telangiectasia, an evolving phenotype
    Chun, HH
    Gatti, RA
    [J]. DNA REPAIR, 2004, 3 (8-9) : 1187 - 1196
  • [10] CEREBRAL WHITE-MATTER CHANGES SUGGESTING LEUKODYSTROPHY IN ATAXIA-TELANGIECTASIA
    CHUNG, EO
    BODENSTEINER, JB
    NOORANI, PA
    SCHOCHET, SS
    [J]. JOURNAL OF CHILD NEUROLOGY, 1994, 9 (01) : 31 - 35