Endogenous and X-ray-induced DNA double strand breaks sensitively activate apoptosis in adult neural stem cells

Abstract

The embryonic neural stem cell compartment is characterised by rapid proliferation from E11 to E16.5, high endogenous DNA double-strand break (DSB) formation and marked sensitivity to undergo 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 (Lig4Y288C), ataxia telangiectasia mutated (Atm−/−) and double mutant Atm−/−/Lig4Y288C mice. We demonstrate that, although DSBs do not arise at high frequency in adult neural stem cells, DSBs that persist endogenously in Lig4Y288C mice or induced by low radiation doses can sensitively activate apoptosis. A temporal analysis shows that DSB levels in Lig4Y288C mice diminish gradually from the embryo to a steady state level in adult mice. The neonatal SVZ compartment of Lig4Y288C 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.