Timing-dependent actions of NGF required for cell differentiation.
Timing-dependent actions of NGF required for cell differentiation.
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DOI：
10.1371/journal.pone.0009011
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发表时间：
2010-02-02
期刊：
影响因子：
3.7
通讯作者：
Kuroda S
中科院分区：
文献类型：
--
作者：
Chung J;Kubota H;Ozaki Y;Uda S;Kuroda S
持续的NGF刺激诱导PC 12细胞分化。然而，为什么需要持续的NGF刺激分化尚不清楚。在这项研究中，我们调查了神经生长因子作用的细胞分化的时间依赖性要求的潜在机制。为了解决时间依赖性的神经生长因子的行动，我们进行了一个不连续的刺激试验，包括第一个短暂的刺激，然后由一个间隔，然后第二个持续的刺激和量化的神经突延伸水平。因此，我们观察到一个时间依赖性的行动，神经生长因子对细胞分化，和不连续的神经生长因子刺激同样诱导分化。第一次刺激不诱导神经突延伸，而第二次刺激诱导快速神经突延伸;因此，第一次刺激可能需要作为先决条件。这些观察结果表明，神经生长因子的作用可以分为两个过程：初始刺激驱动的潜伏过程和第二刺激驱动的延伸过程。潜伏过程似乎需要ERK和转录的活性，但不需要PI 3 K，而延伸过程需要ERK和PI 3 K的活性，但不需要转录。我们还发现，在第一次刺激期间，NGF的活性可以被PACAP替代，但不能被胰岛素、EGF、bFGF或forskolin替代;然而，在第二次刺激期间，NGF的活性不能被这些刺激物中的任何一种替代。这些发现使我们能够使用微阵列识别出专门参与潜伏过程而不是其他过程的潜在基因。这些结果表明，NGF诱导分化的PC 12细胞通过机械不同的过程：ERK驱动和转录依赖性的潜伏过程，和ERK和PI 3 K驱动和转录无关的延伸过程。
Continuous NGF stimulation induces PC12 cell differentiation. However, why continuous NGF stimulation is required for differentiation is unclear. In this study, we investigated the underlying mechanisms of the timing-dependent requirement of NGF action for cell differentiation. To address the timing-dependency of the NGF action, we performed a discontinuous stimulation assay consisting of a first transient stimulation followed by an interval and then a second sustained stimulation and quantified the neurite extension level. Consequently, we observed a timing-dependent action of NGF on cell differentiation, and discontinuous NGF stimulation similarly induced differentiation. The first stimulation did not induce neurite extension, whereas the second stimulation induced fast neurite extension; therefore, the first stimulation is likely required as a prerequisite condition. These observations indicate that the action of NGF can be divided into two processes: an initial stimulation-driven latent process and a second stimulation-driven extension process. The latent process appears to require the activities of ERK and transcription, but not PI3K, whereas the extension-process requires the activities of ERK and PI3K, but not transcription. We also found that during the first stimulation, the activity of NGF can be replaced by PACAP, but not by insulin, EGF, bFGF or forskolin; during the second stimulation, however, the activity of NGF cannot be replaced by any of these stimulants. These findings allowed us to identify potential genes specifically involved in the latent process, rather than in other processes, using a microarray. These results demonstrate that NGF induces the differentiation of PC12 cells via mechanically distinct processes: an ERK-driven and transcription-dependent latent process, and an ERK- and PI3K-driven and transcription-independent extension process.
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