A co-ordinated response to DNA damage activates quiescent neural stem cells in a niche position and age-specific manner.pdf (14.26 MB)
A coordinated DNA damage response promotes adult quiescent neural stem cell activation
journal contribution
posted on 2023-06-09, 14:33 authored by Penny Jeggo, Lara Barazzuol, Limei JuStem 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.
Funding
RISK-IR: Risk, stem cells and tissue kinetics - Ionising radiation (HPA lead); G1009; EUROPEAN UNION; 323267
History
Publication status
- Published
File Version
- Published version
Journal
PLoS BiologyISSN
1544-9173Publisher
Public Library of ScienceExternal DOI
Issue
5Volume
15Page range
1-25Article number
e2001264Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-16First Open Access (FOA) Date
2018-08-16First Compliant Deposit (FCD) Date
2018-08-15Usage metrics
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