Caspases and p53 modulate FOXO3A/Id1 signaling during mouse neural stem cell differentiation.
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 beta-III tubulin and astroglial GFAP to confirm that both processes occurred at approximately 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.
Aranha
Márcia M
MM
iMed.UL, University of Lisbon, Portugal.
Solá
Susana
S
Low
Walter C
WC
Steer
Clifford J
CJ
Rodrigues
Cecília M P
CM
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology*; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3