Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 28, Issue 6, Pages 1049-1059Publisher
WILEY
DOI: 10.1111/j.1460-9568.2008.06420.x
Keywords
aphidicolin; cdk5; NeuroD; rat neural progenitor cell; smad3
Categories
Funding
- Japan Society for the Promotion of Science (JSPS) [16500203, 20500160]
- The Ministry of Education, Culture, Sports, Science and Technology (MECSST)
- Ajinomoto KK
- Japan Brain Foundation
- Grants-in-Aid for Scientific Research [20500160, 16500203] Funding Source: KAKEN
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We have previously demonstrated that a G1/S-phase cell cycle blocker, deferoxamine (DFO), increased the number of new neurons from rat neurosphere cultures, which correlated with prolonged expression of cyclin-dependent kinase (cdk) inhibitor p27(kip1) [ H. J. Kim et al. (2006) Brain Research, 1092, 1-15]. The present study focuses on neuronal differentiation mechanisms following treatment of neural stem/progenitor cells (NPCs) with a G1/S-phase cell cycle blocker. The addition of DFO (0.5 mm) or aphidicolin (Aph) (1.5 mu m) to neurospheres for 8 h, followed by 3 days of differentiation, resulted in an increased number of neurons and neurite outgrowth. DFO induced enhanced expression of transforming growth factor (TGF)-beta 1 and cdk5 at 24 h after differentiation, whereas Aph only increased TGF-beta 1 expression. DFO-induced neurogenesis and neurite outgrowth were attenuated by administration of a cdk5 inhibitor, roscovitine, suggesting that the neurogenic mechanisms differ between DFO and Aph. TGF-beta 1 (10 ng/mL) did not increase neurite outgrowth but rather the number of beta-tubulin III-positive cells, which was accompanied by enhanced p27(kip1) mRNA expression. In addition, TGF-beta receptor type II expression was observed in nestin-positive NPCs. Results indicated that DFO-induced TGF-beta 1 signaling activated smad3 translocation from the cytoplasm to the nucleus. In contrast, TGF-beta 1 signaling inhibition, via a TGF-beta receptor type I inhibitor (SB-505124), resulted in decreased DFO-induced neurogenesis, in conjunction with decreased p27(kip1) protein expression and smad3 translocation to the nucleus. These results suggest that cell cycle arrest during G1/S-phase induces TGF-beta 1 expression. This, in turn, prompts enhanced neuronal differentiation via smad3 translocation to the nucleus and subsequent p27(kip1) activation in NPCs.
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