Caspases and p53 modulate FOXO3A/Id1 signaling during mouse neural stem cell differentiation

Márcia M. Aranha, Susana Solá, Walter C. Low, Clifford J. Steer, Cecélia M P Rodrigues

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Neural stem cells (NSCs) differentiate into neurons and glia, and a large percentage undergoes apoptosis. The engagement and activity of apoptotic pathways may favor either cell death or differentiation. In addition, Akt represses differentiation by up-regulating the inhibitor of differentiation 1 (Id1), through phosphorylation of its repressor FOXO3A. The aim of this study was to investigate the potential cross-talk between apoptosis and proliferation during mouse NSC differentiation. We determined the time of neurogenesis and gliogenesis using neuronal b-III tubulin and astroglial GFAP to confirm that both processes occurred at ∼3 and 8 days, respectively. p-Akt, p-FOXO3A, and Id1 were significantly reduced throughout differentiation. Caspase-3 processing, p53 phosphorylation, and p53 transcriptional activation increased at 3 days of differentiation, with no evidence of apoptosis. Importantly, in cells exposed to the pancaspase inhibitor z-VAD.fmk, p-FOXO3A and Id1 were no longer down-regulated, p53 phosphorylation and transcriptional activation were reduced, while neurogenesis and gliogenesis were significantly delayed. The effect of siRNA-mediated silencing of p53 on FOXO3A/Id1 was similar to that of z-VAD.fmk only at 3 days of differentiation. Interestingly, caspase inhibition further increased the effect of p53 knockdown during neurogenesis. In conclusion, apoptosis-associated factors such as caspases and p53 temporally modulate FOXO3A/Id1 signaling and differentiation of mouse NSCs.

Original languageEnglish (US)
Pages (from-to)748-758
Number of pages11
JournalJournal of Cellular Biochemistry
Volume107
Issue number4
DOIs
StatePublished - Jul 1 2009

Keywords

  • Apoptosis
  • Caspases
  • Differentiation
  • Neural stem cells
  • Proliferation
  • p53

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