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: Lara Barazzuol, Nicole Rickett, Limei Ju, Penny A Jeggo
• Journal: Journal of cell science (J Cell Sci) Vol. 128 Issue 19 Pg. 3597-606 (Oct 01 2015) ISSN: 1477-9137 [Electronic] England
• PMID: 26303202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Topics

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