title: In vivo sensitivity of the embryonic and adult neural stem cell compartments to low-dose radiation.
abstract: The embryonic brain is radiation-sensitive, with cognitive deficits being observed after exposure to low radiation doses. Exposure of neonates to radiation can cause intracranial carcinogenesis. To gain insight into the basis underlying these outcomes, we examined the response of the embryonic, neonatal and adult brain to low-dose radiation, focusing on the neural stem cell compartments. This review summarizes our recent findings. At E13.5-14.5 the embryonic neocortex encompasses rapidly proliferating stem and progenitor cells. Exploiting mice with a hypomorphic mutation in DNA ligase IV (Lig4(Y288C) ), we found a high level of DNA double-strand breaks (DSBs) at E14.5, which we attribute to the rapid proliferation. We observed endogenous apoptosis in Lig4(Y288C) embryos and in WT embryos following exposure to low radiation doses. An examination of DSB levels and apoptosis in adult neural stem cell compartments, the subventricular zone (SVZ) and the subgranular zone (SGZ) revealed low DSB levels in Lig4(Y288C) mice, comparable with the levels in differentiated neuronal tissues. We conclude that the adult SVZ does not incur high levels of DNA breakage, but sensitively activates apoptosis; apoptosis was less sensitively activated in the SGZ, and differentiated neuronal tissues did not activate apoptosis. P5/P15 mice showed intermediate DSB levels, suggesting that DSBs generated in the embryo can be transmitted to neonates and undergo slow repair. Interestingly, this analysis revealed a stage of high endogenous apoptosis in the neonatal SVZ. Collectively, these studies reveal that the adult neural stem cell compartment, like the embryonic counterpart, can sensitively activate apoptosis.
authors.affiliation: Genome Damage and Stability Centre, Life Sciences, University of Sussex, Brighton, East Sussex BN19RQ, UK.
authors.forename: Lara
authors.initials: L
authors.lastname: Barazzuol
authors.affiliation: Genome Damage and Stability Centre, Life Sciences, University of Sussex, Brighton, East Sussex BN19RQ, UK p.a.jeggo@sussex.ac.uk.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000528:radiation effects*; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000378:metabolism; D002451:Cell Compartmentation / Q000528:radiation effects*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D000072481:DNA Ligase ATP / Q000172:deficiency / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000528:radiation effects*; D058953:Neural Stem Cells / Q000166:cytology / Q000528:radiation effects*; D011839:Radiation, Ionizing; D013577:Syndrome
chemical_list: C000607896:Lig4 protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D000072481:DNA Ligase ATP
keywords: DNA damage response; DNA double-strand break repair; low-dose radiation; neural stem cells; radiation sensitivity