Abstract
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 Lig 4 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.
Highlights
DNA double-strand breaks (DSBs) are severe lesions that can cause cell death and/or chromosomal rearrangements
Given that we aimed subsequently to examine apoptosis, which is activated by ataxia telangiectasia mutated (ATM) at DSBs, we examined 53BP1 foci in WT, Lig4Y288C, Atm−/−
Sensitive activation of apoptosis in the adult neural stem cells The embryonic neocortex is characterised by high proliferation from E11 to E16.5, high DSB damage and by sensitivity to DSB-induced apoptosis (Bayer et al, 1991; Gatz et al, 2011; Pontious et al, 2008; Saha et al, 2014)
Summary
DNA double-strand breaks (DSBs) are severe lesions that can cause cell death and/or chromosomal rearrangements. They are the major lethal lesion induced by ionising radiation but can arise from oxidative damage, following replication and during immune development. DNA ligase IV knockout in mice is embryonically lethal owing to extensive neuronal apoptosis around embryonic day (E)13.5 (Barnes et al, 1998; Frank et al, 1998). Hypomorphic mutations in DNA ligase IV confer LIG4 syndrome, which is characterised by immunodeficiency, microcephaly and developmental delay (O’Driscoll et al, 2001). A recent study has proposed that DNA ligase IV deficiency is a common cause of extreme growth failure and microcephaly (Murray et al, 2014)
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