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

Yaniv Assaf, Ronit Galron, Itai Shapira, Anat Nitzan, Tamar Blumenfeld-Katzir, Arieh S. Solomon, Vered Holdengreber, Zhao Qi Wang, Yosef Shiloh, Ari Barzilai

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)181-191
Number of pages11
JournalExperimental Neurology
Volume209
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • MRI
  • Myelin
  • NBS
  • Nbs1 conditional knockout
  • Oligodentrocytes
  • White matter

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