The dynein inhibitor Ciliobrevin D inhibits the bidirectional transport of organelles along sensory axons and impairs NGF-mediated regulation of growth cones and axon branches.
The dynein inhibitor Ciliobrevin D inhibits the bidirectional transport of organelles along sensory axons and impairs NGF-mediated regulation of growth cones and axon branches.
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DOI：
10.1002/dneu.22246
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发表时间：
2015-07
影响因子：
3
通讯作者：
Gallo, Gianluca
中科院分区：
文献类型：
--
作者：
Sainath, Rajiv;Gallo, Gianluca
关键词：
细胞器的轴突运输对于神经元的发育、维持和存活至关重要，并且其功能障碍已经与几种神经退行性疾病有关。轴突的逆行运输是由动力蛋白介导的。在这项研究中，使用胚胎鸡背根神经节神经元，我们调查的影响，纤毛蛋白D，药理动力蛋白抑制剂，轴突细胞器，轴突延伸，神经生长因子（NGF）诱导的分支和生长锥扩张，轴突变薄响应肌动蛋白丝解聚的运输。轴突中线粒体、溶酶体和高尔基体衍生囊泡的实时成像显示，这些细胞器的逆行和顺行运输均被Ciliobrevin D抑制。用纤毛蛋白D治疗可逆地抑制轴突延伸和运输，在治疗的前20分钟内可检测到效果。神经生长因子诱导生长锥扩张，轴突丝状伪足形成和分支。纤毛菌素D阻止了神经生长因子诱导的轴突丝状伪足和分支的形成，但没有生长锥扩张。最后，我们报告说，轴突细胞质发生后，肌动蛋白丝解聚的逆行重组被抑制治疗Ciliobrevin D，这表明在这个过程中的微管为基础的运输的作用，以及Ciliobrevin D加速沃勒变性。本研究确定Ciliobrevin D作为多个轴突细胞器的双向运输的抑制剂，表明这种药物可能是动力蛋白功能研究和轴突运输作用的首次通过分析的有价值的工具。
The axonal transport of organelles is critical for the development, maintenance and survival of neurons, and its dysfunction has been implicated in several neurodegenerative diseases. Retrograde axon transport is mediated by the motor protein dynein. In this study, using embryonic chicken dorsal root ganglion neurons, we investigate the effects of Ciliobrevin D, a pharmacological dynein inhibitor, on the transport of axonal organelles, axon extension, nerve growth factor (NGF)-induced branching and growth cone expansion, and axon thinning in response to actin filament depolymerization. Live imaging of mitochondria, lysosomes and Golgi-derived vesicles in axons revealed that both the retrograde and anterograde transport of these organelles was inhibited by treatment with Ciliobrevin D. Treatment with Ciliobrevin D reversibly inhibits axon extension and transport, with effects detectable within the first 20 minutes of treatment. NGF induces growth cone expansion, axonal filopodia formation and branching. Ciliobrevin D prevented NGF-induced formation of axonal filopodia and branching but not growth cone expansion. Finally, we report that the retrograde reorganization of the axonal cytoplasm which occurs upon actin filament depolymerization is inhibited by treatment with Ciliobrevin D, indicating a role for microtubule based transport in this process, as well as Ciliobrevin D accelerating Wallerian degeneration. This study identifies Ciliobrevin D as an inhibitor of the bi-directional transport of multiple axonal organelles, indicating this drug may be a valuable tool for both the study of dynein function and a first pass analysis of the role of axonal transport.
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DOI：
10.1083/jcb.200807155
发表时间：
2009-04-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fejtova A;Davydova D;Bischof F;Lazarevic V;Altrock WD;Romorini S;Schöne C;Zuschratter W;Kreutz MR;Garner CC;Ziv NE;Gundelfinger ED
通讯作者：
Gundelfinger ED
DOI：
10.1083/jcb.200908075
发表时间：
2009-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ally S;Larson AG;Barlan K;Rice SE;Gelfand VI
通讯作者：
Gelfand VI
影响因子：
2.9
作者：
Engel, Benjamin D.;Ishikawa, Hiroaki;Marshall, Wallace F.
通讯作者：
Marshall, Wallace F.
影响因子：
7.5
作者：
Gennerich A;Vale RD
通讯作者：
Vale RD
DOI：
10.1083/jcb.109.6.3085
发表时间：
1989-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Baas PW;Black MM;Banker GA
通讯作者：
Banker GA