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首页> 外文期刊>The European Journal of Neuroscience >Enhanced neurogenesis from neural progenitor cells with G1/S-phase cell cycle arrest is mediated by transforming growth factor beta1.
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Enhanced neurogenesis from neural progenitor cells with G1/S-phase cell cycle arrest is mediated by transforming growth factor beta1.

机译：G1 / S期细胞周期停滞从神经祖细胞增强的神经发生是通过转化生长因子beta1介导的。

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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 microm) 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)-beta1 and cdk5 at 24 h after differentiation, whereas Aph only increased TGF-beta1 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-beta1 (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-beta1 signaling activated smad3 translocation from the cytoplasm to the nucleus. In contrast, TGF-beta1 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-beta1 expression. This, in turn, prompts enhanced neuronal differentiation via smad3 translocation to the nucleus and subsequent p27(kip1) activation in NPCs.
机译：我们以前已经证明，G1 / S期细胞周期阻滞剂去铁胺（DFO）可以增加大鼠神经球培养物中新神经元的数量，这与周期蛋白依赖性激酶（cdk）抑制剂p27（kip1）的延长表达有关[ H。 J.金等。 （2006）Brain Research，1092，1-15]。本研究集中在用G1 / S期细胞周期阻滞剂治疗神经干/祖细胞（NPC）之后的神经元分化机制。在神经球中添加DFO（0.5 mm）或蚜虫（Aph）（1.5 microm）8小时，然后进行3天的分化，导致神经元数量增多和神经突向外生长。 DFO诱导分化后24小时增强了转化生长因子（TGF）-beta1和cdk5的表达，而Aph仅提高了TGF-beta1的表达。通过施用cdk5抑制剂roscovitine可以减轻DFO诱导的神经发生和神经突向外生长，表明DFO和Aph之间的神经发生机制不同。 TGF-beta1（10 ng / mL）不会增加神经突向外生长，但会增加β-微管蛋白III阳性细胞的数量，并伴随增强的p27（kip1）mRNA表达。另外，在巢蛋白阳性的NPC中观察到II型TGF-β受体表达。结果表明，DFO诱导的TGF-β1信号激活了smad3从细胞质到细胞核的转运。相反，通过I型TGF-β受体抑制剂（SB-505124），TGF-β1信号传导抑制导致DFO诱导的神经发生减少，同时p27（kip1）蛋白表达减少和smad3易位。这些结果表明在G1 / S期的细胞周期停滞诱导TGF-beta1表达。反过来，这促使通过smad3易位到核以及随后在NPC中激活p27（kip1）来增强神经元分化。

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