Notch Activation Induces Neurite Remodeling and Functional Modifications in SH-SY5Y Neuronal Cells
Notch Activation Induces Neurite Remodeling and Functional Modifications in SH-SY5Y Neuronal Cells
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DOI：
10.1002/dneu.20710
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发表时间：
2009-05-01
影响因子：
3
通讯作者：
Memo, Maurizio
中科院分区：
文献类型：
--
作者：
Ferrari-Toninelli, Giulia;Bonini, Sara Anna;Memo, Maurizio
Notch蛋白被认为是胚胎发育过程中神经元命运的关键调节因子，但其在成人大脑中的功能仍然是未知的。我们先前已经证明，Notch途径刺激增加微管稳定性，随后神经元形态重塑，神经突静脉曲张损失，较厚的神经炎和扩大的生长锥。在这里，我们表明，神经突重塑是一个动态的事件，依赖于转录和翻译，并与功能的影响。将分化的人SH-SY 5 Y神经母细胞瘤细胞暴露于Notch配体Jagged 1诱导所有沿着神经突的静脉曲张丧失，伴随着突触前囊泡的重新分布和神经递质释放的减少。如通过时间推移数字成像所评估的，神经突形态的动态变化是快速可逆的，并且依赖于Notch信号通路的激活。事实上，它是通过抑制蛋白水解的γ-分泌酶或转录机制来阻止的，并且通过转染Notch的细胞内结构域来模拟。在用Jagged 1处理一小时后，几个基因下调。这些基因中的许多编码已知参与蛋白质合成的蛋白质。这些数据表明，在成年神经元中，Notch通路激活转录程序，调节神经元突触前区室中的静脉曲张形成和静脉曲张损失之间的平衡，涉及结构和功能蛋白的表达和再分布。(C)2009 Wiley Periodicals，Inc.开发神经生物学69：378-391，2009
Notch proteins are definitely recognized as key regulators of the neuronal fate during embryo development, but their function in the adult brain is still largely unknown. We have previously demonstrated that Notch pathway stimulation increases microtubules stability followed by the remodeling of neuronal morphology with neurite varicosities loss, thicker neuritis, and enlarged growth cones. Here we show that the neurite remodeling is a dynamic event, dependent on transcription and translation, and with functional implications. Exposure of differentiated human SH-SY5Y neuroblastoma cells to the Notch ligand Jagged1 induces varicosities loss all along the neurites, accompanied by the redistribution of presynaptic vesicles and the decrease in neurotransmitters release. As evaluated by time lapse digital imaging, dynamic changes in neurite morphology were rapidly reversible and dependent on the activation of the Notch signaling pathway. In fact, it was prevented by the inhibition of the proteolytic gamma-secretase enzyme or the transcription machinery, and was mimicked by the transfection of the intracellular domain of Notch. One hour after treatment with Jagged1, several genes were downregulated. Many of these genes encode proteins that are known to be involved in protein synthesis. These data suggest that in adult neurons, Notch pathway activates a transcriptional program that regulates the equilibrium between varicosities formation and varicosities loss in the neuronal presynaptic compartment involving the expression and redistribution of both structural and functional proteins. (C) 2009 Wiley Periodicals, Inc. Develop Neurobiol 69: 378-391, 2009