Caspase Regulation of Genotoxin-Induced Neural Precursor Cell Death

Cleta D'Sa, Barbara J. Klocke, Francesco Cecconi, Tulia Lindsten, Craig B. Thompson, Stanley J. Korsmeyer, Richard A. Flavell, Kevin A. Roth

Research output: Contribution to journalArticle

Abstract

Neural precursor cells (NPCs) critically regulate brain morphogenesis and recent studies have revealed an unexpectedly high frequency of NPC chromosomal abnormalities and apoptosis in the developing brain. We have shown previously that the apoptotic response of NPCs to genotoxic agents is dependent on p53 and caspase-9, but not Bax or caspase-3 expression. In this study, we found that NPCs deficient in Apaf-1, or both the pro-apoptotic multidomain Bcl-2 family members Bax and Bak, were resistant to cytosine arabinoside and γ-irradiation-induced apoptosis. Inhibitors of gene transcription, protein translation, and caspase activity also blocked genotoxin-induced NPC apoptosis. Although caspase-3 and caspase-6 were both cleaved in response to DNA damage, neither of these effector caspases was critical for apoptosis. Genotoxin-induced NPC death was accompanied by the generation of reactive oxygen species and could be inhibited by several known antioxidants. Conversely, DNA damage-induced reactive oxygen species generation was inhibited significantly by gene disruption of p53, Apaf-1, or caspase-9, and combined deficiency of Bax and Bak, but not by caspase-3 or caspase-6 deficiency. These studies suggest that caspase-9 activation is both necessary and sufficient for genotoxin-induced neural precursor cell reactive oxygen species generation and death.

Original languageEnglish
Pages (from-to)435-445
Number of pages11
JournalJournal of Neuroscience Research
Volume74
Issue number3
DOIs
Publication statusPublished - Nov 1 2003

Keywords

  • Apoptosis
  • Bax
  • Bcl-2
  • P53
  • Programmed cell death

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    D'Sa, C., Klocke, B. J., Cecconi, F., Lindsten, T., Thompson, C. B., Korsmeyer, S. J., Flavell, R. A., & Roth, K. A. (2003). Caspase Regulation of Genotoxin-Induced Neural Precursor Cell Death. Journal of Neuroscience Research, 74(3), 435-445. https://doi.org/10.1002/jnr.10738