GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules
GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules
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DOI：
10.1101/gad.17015911
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发表时间：
2011-09-15
影响因子：
10.5
通讯作者：
Zhou, Feng-Quan
中科院分区：
文献类型：
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作者：
Hur, Eun-Mi;Saijilafu;Zhou, Feng-Quan
神经元中糖原合成酶激酶3 （GSK3）活性的抑制产生多效性结果，引起轴突生长促进和抑制。先前的研究表明，特定的GSK3底物，如大肠腺瘤性息肉病（APC）和崩溃蛋白反应介质蛋白2 (CRMP2)，通过调节轴突微管（MTs）的稳定性来支持轴突生长，但传递轴突生长抑制的底物和机制尚不清楚。本研究表明，最初被鉴定为MT +端结合蛋白的CLIP（细胞质连接蛋白）相关蛋白（CLASP）在神经生长锥中显示出正端结合和晶格结合活性，并揭示了两种MT结合活性以相反的方式调节轴突生长。晶格结合活性通过抑制GSK3活性来抑制轴突生长，从而阻止MT突出到生长锥体的外围，而正端结合特性通过稳定轴突MT的生长末端来支持轴突的延伸。我们提出了一个模型，该模型通过协调生长锥体MT的稳定性和结构，CLASP通过转导GSK3活性水平来差异控制轴突生长。
Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs.