c-Jun NH2-terminal Kinase (JNK)-interacting Protein-3 (JIP3) Regulates Neuronal Axon Elongation in a Kinesin- and JNK-dependent Manner*
c-Jun NH2-terminal Kinase (JNK)-interacting Protein-3 (JIP3) Regulates Neuronal Axon Elongation in a Kinesin- and JNK-dependent Manner*
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DOI：
10.1074/jbc.m113.464453
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Tao Sun;Nuo Yu;Lu-Kai Zhai;Na Li;Chao Zhang;Liang Zhou;Zhuo Huang;Xingyu Jiang;Ying Shen-Ying-Sh
中科院分区：
文献类型：
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作者：
Tao Sun;Nuo Yu;Lu-Kai Zhai;Na Li;Chao Zhang;Liang Zhou;Zhuo Huang;Xingyu Jiang;Ying Shen-Ying-Sh
背景：除了轴突分支外，JIP3在轴突规范和延长中的作用尚不清楚。结果：JIP3局部激活轴突顶端的JNK-cofilin通路，从而促进轴突的延长。结论：JIP3是轴突伸长所必需的。意义：这些结果促进了我们对JIP3在轴突发育中的作用的理解。神经元极性的发展对于在大脑中建立准确的神经元回路模式是必不可少的。然而，对神经元发育过程中控制轴突快速伸长的潜在分子机制知之甚少。在这里，我们报道了c-Jun氨基末端激酶(JNK)相互作用蛋白-3(JIP3)在轴突发育的关键期在轴突顶端高表达。利用获得和丧失功能的方法、免疫荧光分析和宫内电穿孔，我们发现JIP3可以在体内促进原代海马神经元和皮质神经元的轴突延长。我们使用JIP3的几个缺失突变体进一步证明了JIP3以动蛋白和JNK依赖的方式促进轴突延长。接下来，我们证明了通过Kinesin成功地将JIP3转运到轴突末端是增强该区域JNK磷酸化从而促进轴突延长的先决条件，从而构成了JIP3顺行转运与远端轴突和轴突延长的JNK信号偶联的新机制。最后，我们的免疫荧光数据表明，轴突顶端JNK的激活通过调节cofilin活性和肌动蛋白细丝动力学来促进轴突延长。这些发现可能对我们理解神经元轴突在发育过程中的延长有重要的意义。
Background: The role of JIP3 in axon specification and elongation in addition to axon branching remains unknown. Results: JIP3 locally activates the JNK-cofilin pathway at axon tips and thus enhances axon elongation. Conclusion: JIP3 is essential for axon elongation. Significance: These results advance our understanding of the role of JIP3 in axon development. The development of neuronal polarity is essential for the establishment of the accurate patterning of neuronal circuits in the brain. However, little is known about the underlying molecular mechanisms that control rapid axon elongation during neuronal development. Here, we report that c-Jun NH2-terminal kinase (JNK)-interacting protein-3 (JIP3) is highly expressed at axon tips during the critical period for axon development. Using gain- and loss-of-function approaches, immunofluorescence analysis, and in utero electroporation, we find that JIP3 can enhance axon elongation in primary hippocampal neurons and cortical neurons in vivo. We further demonstrate that JIP3 promotes axon elongation in a kinesin- and JNK-dependent manner using several deletion mutants of JIP3. Next, we demonstrate that the successful transportation of JIP3 to axon tips by kinesin is a prerequisite for enhancing JNK phosphorylation in this area and therefore promotes axon elongation, constituting a novel mechanism for coupling JIP3 anterograde transport with JNK signaling at the distal axons and axon elongation. Finally, our immunofluorescence data suggest that the activation of JNK at axon tips facilitates axon elongation by modulating cofilin activity and actin filament dynamics. These findings may have important implications for our understanding of neuronal axon elongation during development.