A coordinated DNA damage response promotes adult quiescent neural stem cell activation

Jeggo, Penny, Barazzuol, Lara and Ju, Limei (2017) A coordinated DNA damage response promotes adult quiescent neural stem cell activation. PLoS Biology, 15 (5). e2001264 1-25. ISSN 1544-9173

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Abstract

Stem and differentiated cells frequently differ in their response to DNA damage, which can determine tissue sensitivity. By exploiting insight into the spatial arrangement of subdomains within the adult neural subventricular zone (SVZ) in vivo, we show distinct responses to ionising radiation (IR) between neural stem and progenitor cells. Further, we reveal different DNA damage responses between neonatal and adult neural stem cells (NSCs). Neural progenitors (transit amplifying cells and neuroblasts) but not NSCs (quiescent and activated) undergo apoptosis after 2 Gy IR. This response is cell type- rather than proliferationdependent and does not appear to be driven by distinctions in DNA damage induction or repair capacity. Moreover, exposure to 2 Gy IR promotes proliferation arrest and differentiation in the adult SVZ. These 3 responses are ataxia telangiectasia mutated (ATM)- dependent and promote quiescent NSC (qNSC) activation, which does not occur in the subdomains that lack progenitors. Neuroblasts arising post-IR derive from activated qNSCs rather than irradiated progenitors, minimising damage compounded by replication or mitosis. We propose that rather than conferring sensitive cell death, apoptosis is a form of rapid cell death that serves to remove damaged progenitors and promote qNSC activation. Significantly, analysis of the neonatal (P5) SVZ reveals that although progenitors remain sensitive to apoptosis, they fail to efficiently arrest proliferation. Consequently, their repopulation occurs rapidly from irradiated progenitors rather than via qNSC activation.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Depositing User: Penny Jeggo
Date Deposited: 16 Aug 2018 10:35
Last Modified: 02 Jul 2019 14:50
URI: http://sro.sussex.ac.uk/id/eprint/77868

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Project NameSussex Project NumberFunderFunder Ref
RISK-IR: Risk, stem cells and tissue kinetics - Ionising radiation (HPA lead)G1009EUROPEAN UNION323267