Conditional inactivation of the NBS1 gene in the mouse central nervous system leads to neurodegeneration and disorganization of the visual system

Koby Baranes, Dorit Raz-Prag, Anat Nitzan, Ronit Galron, Ruth Ashery-Padan, Ygal Rotenstreich, Yaniv Assaf, Yosef Shiloh, Zhao Qi Wang, Ari Barzilai, Arieh S. Solomon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 the human NBS1, Nbs1, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. Here we report that conditional targeted disruption of the murine NBS1 gene in the CNS results in mal-development, degeneration, disorganization and dysfunction of the murine visual system, especially in the optic nerve. Nbs1 deletion resulted in reduced diameters of Nbs1-CNS-Δ eye and optic nerve. MRI analysis revealed defective white matter development and organization. Nbs1 inactivation altered the morphology and organization of the glial cells. Interestingly, at the age of two-month-old the levels of the axonal guidance molecule semaphorin-3A and its receptor neuropilin-1 were up-regulated in the retina of the mutant mice, a typical injury response. Electroretinogram analysis revealed marked reduction in a- and b-waves, indicative of decreased retinal function. Our study points to a novel role for Nbs1 in the development, organization and function of the visual system.

Original languageEnglish
Pages (from-to)24-32
Number of pages9
JournalExperimental Neurology
Volume218
Issue number1
DOIs
StatePublished - Jul 2009

Funding

FundersFunder number
A-T Ease Foundation
German-Israel Foundation
A-T Children's Project
Dr. Ralph and Marian Falk Medical Research Trust
Association for International Cancer Research
Deutsche Forschungsgemeinschaft
United States-Israel Binational Science Foundation
Israel Science Foundation
Medical Research Foundation

    Keywords

    • Ataxia telangiectasia (A-T)
    • MRI
    • Myelin
    • Nbs1
    • Nijmegen breakage syndrome (NBS)
    • Oligodentrocytes
    • White matter

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