title: Low levels of endogenous or X-ray-induced DNA double-strand breaks activate apoptosis in adult neural stem cells.
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.
authors: Genome Damage and Stability Centre, University of Sussex, East Sussex BN19RQ, UK.
authors: Lara
authors: L
authors: Barazzuol
authors: Genome Damage and Stability Centre, University of Sussex, East Sussex BN19RQ, UK.
authors: Nicole
authors: N
authors: Rickett
authors: Genome Damage and Stability Centre, University of Sussex, East Sussex BN19RQ, UK.
authors: Limei
authors: L
authors: Ju
authors: Genome Damage and Stability Centre, University of Sussex, East Sussex BN19RQ, UK p.a.jeggo@sussex.ac.uk.
authors: Penny A
authors: PA
authors: Jeggo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D005260:Female; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000528:radiation effects*; D014965:X-Rays
keywords: Apoptosis; DNA double-strand break repair; Neural stem cell; Radiation sensitivity