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

Lara Barazzuol, Limei Ju, Penny A. Jeggo*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    36 Citations (Scopus)
    337 Downloads (Pure)

    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.

    Original languageEnglish
    Article numbere2001264
    Number of pages25
    JournalPLOS BIOLOGY
    Volume15
    Issue number5
    DOIs
    Publication statusPublished - 10-May-2017

    Keywords

    • SUBVENTRICULAR ZONE
    • MAMMALIAN BRAIN
    • RADIATION
    • CYCLE
    • DIFFERENTIATION
    • IRRADIATION
    • MICE
    • ORGANIZATION
    • CHILDHOOD
    • APOPTOSIS

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