TY - JOUR
T1 - MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome
AU - Assaf, Yaniv
AU - Galron, Ronit
AU - Shapira, Itai
AU - Nitzan, Anat
AU - Blumenfeld-Katzir, Tamar
AU - Solomon, Arieh S.
AU - Holdengreber, Vered
AU - Wang, Zhao Qi
AU - Shiloh, Yosef
AU - Barzilai, Ari
N1 - Funding Information:
The MRI scanner used in this study was purchased with a grant from The Israel Science Foundation and operated under the Raymond and Beverly Sackler Center for Biophysics, Tel Aviv University and The Alfredo Federico Strauss Center for Computational Neuro-Imaging, Tel Aviv University. This work was supported by research grants from the A-T Children's Project, the Israel Science Foundation and the US-Israel Binational Science Foundation (to A.B.), and The A-T Medical Research Foundation, The A-T Children's Project, the A-T Medical Research Trust and the A-T Ease Foundation (to Y.S.). ZQW is supported by the Association for International Cancer Research (AICR) UK.
PY - 2008/1
Y1 - 2008/1
N2 - Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (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 T2-weighted magnetic resonance, we found that the brains of the mutant mice (Nbs1-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 GalC in Nbs1-CNS-del brains, indicating defects in myelin formation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of Nbs1 in the development and organization of the white matter.
AB - Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (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 T2-weighted magnetic resonance, we found that the brains of the mutant mice (Nbs1-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 GalC in Nbs1-CNS-del brains, indicating defects in myelin formation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of Nbs1 in the development and organization of the white matter.
KW - MRI
KW - Myelin
KW - NBS
KW - Nbs1 conditional knockout
KW - Oligodentrocytes
KW - White matter
UR - http://www.scopus.com/inward/record.url?scp=37549035481&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2007.09.021
DO - 10.1016/j.expneurol.2007.09.021
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:37549035481
SN - 0014-4886
VL - 209
SP - 181
EP - 191
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -