Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1

Nature Neuroscience volume 12, pages 973–980 (2009)Cite this article

Abstract

Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of an Xrcc1 conditional mouse.
Figure 2: Xrcc1Nes-cre cerebellar granule neurons are DNA repair deficient.
Figure 3: The Xrcc1-deficient brain accumulates DNA damage in mature neurons.
Figure 4: Interneurons are missing in the Xrcc1Nes-cre cerebellum.
Figure 5: Differentiating interneurons are decreased in the Xrcc1Nes-cre cerebellum.
Figure 6: Cell cycle arrest in response to DNA damage in the Xrcc1Nes-cre cerebellum.
Figure 7: Interneuron loss in the Xrcc1-null cerebellum is dependent on p53.
Figure 8: Loss of Xrcc1 affects hippocampal homeostasis.

Similar content being viewed by others

References

  1. McKinnon, P.J. DNA repair deficiency and neurological disease. Nat. Rev. Neurosci. 10, 100–112 (2009).

    Article  CAS  Google Scholar 

  2. McKinnon, P.J. & Caldecott, K.W. DNA strand break repair and human genetic disease. Annu. Rev. Genomics Hum. Genet. 8, 37–55 (2007).

    Article  CAS  Google Scholar 

  3. Rass, U., Ahel, I. & West, S.C. Defective DNA repair and neurodegenerative disease. Cell 130, 991–1004 (2007).

    Article  CAS  Google Scholar 

  4. Ahel, I. et al. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Nature 443, 713–716 (2006).

    Article  CAS  Google Scholar 

  5. El-Khamisy, S.F. et al. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434, 108–113 (2005).

    Article  CAS  Google Scholar 

  6. Moreira, M.C. et al. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat. Genet. 29, 189–193 (2001).

    Article  CAS  Google Scholar 

  7. Takashima, H. et al. Mutation of TDP1, encoding a topoisomerase I–dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat. Genet. 32, 267–272 (2002).

    Article  CAS  Google Scholar 

  8. Tebbs, R.S. et al. Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Dev. Biol. 208, 513–529 (1999).

    Article  CAS  Google Scholar 

  9. Tallquist, M.D. & Soriano, P. Epiblast-restricted Cre expression in MORE mice: a tool to distinguish embryonic vs. extra-embryonic gene function. Genesis 26, 113–115 (2000).

    Article  CAS  Google Scholar 

  10. Caldecott, K.W. DNA single-strand break repair and spinocerebellar ataxia. Cell 112, 7–10 (2003).

    Article  CAS  Google Scholar 

  11. Frappart, P.O., Lee, Y., Lamont, J. & McKinnon, P.J. BRCA2 is required for neurogenesis and suppression of medulloblastoma. EMBO J. 26, 2732–2742 (2007).

    Article  CAS  Google Scholar 

  12. Shull, E.R. et al. Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes Dev. 23, 171–180 (2009).

    Article  CAS  Google Scholar 

  13. Caldecott, K.W., McKeown, C.K., Tucker, J.D., Ljungquist, S. & Thompson, L.H. An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III. Mol. Cell. Biol. 14, 68–76 (1994).

    Article  CAS  Google Scholar 

  14. Kulkarni, A., McNeill, D.R., Gleichmann, M., Mattson, M.P. & Wilson, D.M.,, III. XRCC1 protects against the lethality of induced oxidative DNA damage in nondividing neural cells. Nucleic Acids Res. 36, 5111–5121 (2008).

    Article  CAS  Google Scholar 

  15. Rogakou, E.P., Pilch, D.R., Orr, A.H., Ivanova, V.S. & Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    Article  CAS  Google Scholar 

  16. Sedelnikova, O.A., Pilch, D.R., Redon, C. & Bonner, W.M. Histone H2AX in DNA damage and repair. Cancer Biol. Ther. 2, 233–235 (2003).

    Article  CAS  Google Scholar 

  17. Barmack, N.H. & Yakhnitsa, V. Functions of interneurons in mouse cerebellum. J. Neurosci. 28, 1140–1152 (2008).

    Article  CAS  Google Scholar 

  18. Sillitoe, R.V. & Joyner, A.L. Morphology, molecular codes and circuitry produce the three-dimensional complexity of the cerebellum. Annu. Rev. Cell Dev. Biol. 23, 549–577 (2007).

    Article  CAS  Google Scholar 

  19. Eccles, J.C. Neurogenesis and morphogenesis in the cerebellar cortex. Proc. Natl. Acad. Sci. USA 66, 294–301 (1970).

    Article  CAS  Google Scholar 

  20. Weisheit, G. et al. Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur. J. Neurosci. 24, 466–478 (2006).

    Article  Google Scholar 

  21. Watanabe, D. et al. Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination. Cell 95, 17–27 (1998).

    Article  CAS  Google Scholar 

  22. Englund, C. et al. Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J. Neurosci. 26, 9184–9195 (2006).

    Article  CAS  Google Scholar 

  23. Yamanaka, H., Yanagawa, Y. & Obata, K. Development of stellate and basket cells and their apoptosis in mouse cerebellar cortex. Neurosci. Res. 50, 13–22 (2004).

    Article  Google Scholar 

  24. Weyer, A. & Schilling, K. Developmental and cell type–specific expression of the neuronal marker NeuN in the murine cerebellum. J. Neurosci. Res. 73, 400–409 (2003).

    Article  CAS  Google Scholar 

  25. Rakic, P. Kinetics of proliferation and latency between final cell division and onset of differentiation of cerebellar stellate and basket neurons. J. Comp. Neurol. 147, 523–546 (1973).

    Article  CAS  Google Scholar 

  26. Lee, A. et al. Isolation of neural stem cells from the postnatal cerebellum. Nat. Neurosci. 8, 723–729 (2005).

    Article  CAS  Google Scholar 

  27. Kenney, A.M. & Segal, R.A. Subtracting the Math: prominin-positive cerebellar stem cells in white matter. Nat. Neurosci. 8, 699–701 (2005).

    Article  CAS  Google Scholar 

  28. Zhang, L. & Goldman, J.E. Generation of cerebellar interneurons from dividing progenitors in white matter. Neuron 16, 47–54 (1996).

    Article  Google Scholar 

  29. Maricich, S.M. & Herrup, K. Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J. Neurobiol. 41, 281–294 (1999).

    Article  CAS  Google Scholar 

  30. Lee, Y. & McKinnon, P.J. Responding to DNA double strand breaks in the nervous system. Neuroscience 145, 1365–1374 (2007).

    Article  CAS  Google Scholar 

  31. Lee, Y. & McKinnon, P.J. DNA ligase IV suppresses medulloblastoma formation. Cancer Res. 62, 6395–6399 (2002).

    CAS  PubMed  Google Scholar 

  32. Orii, K.E., Lee, Y., Kondo, N. & McKinnon, P.J. Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. Proc. Natl. Acad. Sci. USA 103, 10017–10022 (2006).

    Article  CAS  Google Scholar 

  33. Lumpkin, E.A. et al. Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr. Patterns 3, 389–395 (2003).

    Article  CAS  Google Scholar 

  34. McNamara, J.O., Huang, Y.Z. & Leonard, A.S. Molecular signaling mechanisms underlying epileptogenesis. Sci. STKE 2006, re12 (2006).

    Article  Google Scholar 

  35. Aronica, E. & Gorter, J.A. Gene expression profile in temporal lobe epilepsy. Neuroscientist 13, 100–108 (2007).

    Article  CAS  Google Scholar 

  36. Morgan, J.I., Cohen, D.R., Hempstead, J.L. & Curran, T. Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237, 192–197 (1987).

    Article  CAS  Google Scholar 

  37. Frappart, P.O. & McKinnon, P.J. Ataxia-telangiectasia and related diseases. Neuromolecular Med. 8, 495–511 (2006).

    Article  CAS  Google Scholar 

  38. Goldowitz, D. & Hamre, K. The cells and molecules that make a cerebellum. Trends Neurosci. 21, 375–382 (1998).

    Article  CAS  Google Scholar 

  39. Wang, V.Y. & Zoghbi, H.Y. Genetic regulation of cerebellar development. Nat. Rev. Neurosci. 2, 484–491 (2001).

    Article  CAS  Google Scholar 

  40. Sotelo, C. Cellular and genetic regulation of the development of the cerebellar system. Prog. Neurobiol. 72, 295–339 (2004).

    Article  CAS  Google Scholar 

  41. Leto, K., Carletti, B., Williams, I.M., Magrassi, L. & Rossi, F. Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J. Neurosci. 26, 11682–11694 (2006).

    Article  CAS  Google Scholar 

  42. Kastan, M.B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    Article  CAS  Google Scholar 

  43. Glickstein, S.B. et al. Selective cortical interneuron and GABA deficits in cyclin D2–null mice. Development 134, 4083–4093 (2007).

    Article  CAS  Google Scholar 

  44. Huard, J.M., Forster, C.C., Carter, M.L., Sicinski, P. & Ross, M.E. Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 126, 1927–1935 (1999).

    CAS  PubMed  Google Scholar 

  45. Howell, O.W. et al. Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus. Neurobiol. Dis. 26, 174–188 (2007).

    Article  CAS  Google Scholar 

  46. Baraban, S.C. Neuropeptide Y and epilepsy: recent progress, prospects and controversies. Neuropeptides 38, 261–265 (2004).

    Article  CAS  Google Scholar 

  47. Caldecott, K.W. XRCC1 and DNA strand break repair. DNA Repair (Amst.) 2, 955–969 (2003).

    Article  CAS  Google Scholar 

  48. Soutoglou, E. & Misteli, T. Activation of the cellular DNA damage response in the absence of DNA lesions. Science 320, 1507–1510 (2008).

    Article  CAS  Google Scholar 

  49. Hatten, M.E. Neuronal regulation of astroglial morphology and proliferation in vitro. J. Cell Biol. 100, 384–396 (1985).

    Article  CAS  Google Scholar 

  50. Katyal, S. et al. TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO J. 26, 4720–4731 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Hartwell Center for biotech support, the Transgenic core facility for blastocyst injections, the Animal Imaging core for magnetic resonance imaging analysis and J. Zhao for genotyping. P.J.M. is supported by the US National Institutes of Health (NS-37956 and CA-21765), the Cancer Center Support Grant (P30 CA21765) and the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital. K.W.C. is supported by the Medical Research Council (Grants G0600776 & G0400959) and by the European Union Integrated Project on DNA Repair. S.K. is a Neoma Boadway AP Endowed Fellow and S.F.E.-K. is supported by the Wellcome Trust (Grant 085284).

Author information

Authors and Affiliations

  1. Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Youngsoo Lee, Sachin Katyal, Yang Li, Helen R Russell & Peter J McKinnon

  2. Genome Damage and Stability Unit, University of Sussex, Brighton, UK

    Sherif F El-Khamisy & Keith W Caldecott

  3. Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Sherif F El-Khamisy

Authors
  1. Youngsoo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sachin Katyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sherif F El-Khamisy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Helen R Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keith W Caldecott
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter J McKinnon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y. Lee and S.K. performed all experiments characterizing the Xrcc1-deficient mouse and contributed to writing the manuscript. Y. Li and H.R.R. generated the mouse model and were responsible for colony production and maintenance with assistance from S.K. and Y. Lee. S.F.E.-K. and K.W.C. designed and performed experiments and contributed to preparation of the manuscript. P.J.M. was project leader and produced the final version of the manuscript.

Corresponding author

Correspondence to Peter J McKinnon.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Table 1 (PDF 1859 kb)

Supplementary Movie 1

Xrcc1 movie. (MOV 5122 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, Y., Katyal, S., Li, Y. et al. The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1. Nat Neurosci 12, 973–980 (2009). https://doi.org/10.1038/nn.2375

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2375

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing