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

✍ Scribed by Márcia M. Aranha; Susana Solá; Walter C. Low; Clifford J. Steer; Cecília M.P. Rodrigues

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 438 KB
• Volume: 107
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.22172

✦ Synopsis

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 β‐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. J. Cell. Biochem. 107: 748–758, 2009. © 2009 Wiley‐Liss, Inc.