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

  • Barazzuol L
  • Rickett N
  • Ju L
  • et al.
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Abstract

© 2015. 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 showsthat 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.

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Barazzuol, L., Rickett, N., Ju, L., & Jeggo, P. A. (2015). Low levels of endogenous or X-ray-induced DNA double-strand breaks activate apoptosis in adult neural stem cells. Journal of Cell Science, 128(19), 3597–3606. https://doi.org/10.1242/jcs.171223

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