Low levels of endogenous or X-ray-induced DNA double-strand breaks activate apoptosis in adult neural stem cells

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Abstract

The embryonic neural stem cell compartment is characterised by rapid proliferation from embryonic day (E)11 to E16.5, high endogenous DNA double-strand break (DSB) formation and sensitive activation of apoptosis. Here, we ask whether DSBs arise in the adult neural stem cell compartments, the sub-ventricular zone (SVZ) of the lateral ventricles and the sub-granular zone (SGZ) of the hippocampal dentate gyrus, and whether they activate apoptosis. We used mice with a hypomorphic mutation in DNA ligase IV (Lig4(Y288C)), ataxia telangiectasia mutated (Atm(-/-)) and double mutant Atm(-/-)/Lig4(Y288C) mice. We demonstrate that, although DSBs do not arise at a high frequency in adult neural stem cells, the low numbers of DSBs that persist endogenously in Lig4(Y288C) mice or that are induced by low radiation doses can activate apoptosis. A temporal analysis shows that DSB levels in Lig4(Y288C) mice diminish gradually from the embryo to a steady state level in adult mice. The neonatal SVZ compartment of Lig4(Y288C) mice harbours diminished DSBs compared to its differentiated counterpart, suggesting a process selecting against unfit stem cells. Finally, we reveal high endogenous apoptosis in the developing SVZ of wild-type newborn mice.

Original languageEnglish
Pages (from-to)3597-606
Number of pages10
JournalJournal of Cell Science
Volume128
Issue number19
DOIs
Publication statusPublished - 1-Oct-2015
Externally publishedYes

Keywords

  • Animals
  • Apoptosis/genetics
  • Cells, Cultured
  • DNA Breaks, Double-Stranded/radiation effects
  • Female
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Neural Stem Cells/radiation effects
  • X-Rays

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