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An essential function for NBS1 in the prevention of ataxia and cerebellar defects

Nature Medicine volume 11, pages 538–544 (2005)Cite this article

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Abstract

Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia–like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.

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Figure 1: Disruption of the Nbn gene in embryonic stem and neuronal cells in mice.
Figure 2: Ataxia, microcephaly and cerebellar developmental defects in Nbn-CNS-del mice.
Figure 4: ATM-mediated p53 activation in Nbn-CNS-del neural cells.
Figure 3: Characterization of Nbn-deficient neural cells in vitro.
Figure 5: p53 deficiency rescues growth retardation and neurogenesis defects of Nbn-CNS-del mice.

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  1. NOTE: In the version of this article initially published online, labels in Fig. 5a and b were incorrect. This mistake has been corrected for the HTML and print versions of the article.

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Acknowledgements

We thank D. Galendo for her excellent assistance in the maintenance of the animal colonies, and C. Carreira, G. Hildebrand, N. Lyandrat and S. Roche for their excellent technical assistance. We also thank Y. Shiloh, M. Tommasino and E. F. Wagner for critical reading of the manuscript. We are grateful to J. Cheney and F. Corry for editing the manuscript. P.-O. Frappart is a recipient of a fellowship from the Comité Départmental de la Ligue Nationale contre le Cancer de Haute-Savoie (2000–2002), the Association de la Recherche pour le Cancer (ARC) (2002–2003) and the Ligue Nationale contre le Cancer (2004). This work was supported by the Deutsche Forschungsgemeinschaft (SFB577).

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Authors and Affiliations

  1. International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, Lyon, 69008, France

    Pierre-Olivier Frappart, Wei-Min Tong, Zdenko Herceg & Zhao-Qi Wang

  2. Institute of Human Genetics, Charité-Campus-Virchow, Humboldt Universitaet zu Berlin, Augustenburger Platz 1, Berlin, D-13353, Germany

    Ilja Demuth & Martin Digweed

  3. Institut für Neuropathologie, UniversitätsSpital Zürich, Schmelzbergstr, 12 CH-809, Zürich, Switzerland

    Ivan Radovanovic & Adriano Aguzzi

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  1. Pierre-Olivier Frappart
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Correspondence to Zhao-Qi Wang.

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Supplementary information

Supplementary Fig. 1

Phenotypic and molecular analysis of Nbn-CNS-del mice. (PDF 166 kb)

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Frappart, PO., Tong, WM., Demuth, I. et al. An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nat Med 11, 538–544 (2005). https://doi.org/10.1038/nm1228

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