A role for myosin VI in the localization of axonal proteins.
A role for myosin VI in the localization of axonal proteins.
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DOI：
10.1371/journal.pbio.1001021
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发表时间：
2011-03
期刊：
影响因子：
9.8
通讯作者：
Arnold DB
中科院分区：
文献类型：
--
作者：
Lewis TL Jr;Mao T;Arnold DB
在神经元中，囊泡结合膜蛋白的极化运输导致了轴突和树突不同的分子组成和功能特性。尽管它们在形成神经元形态和功能方面发挥着核心作用，但令人惊讶的是，人们对介导神经元蛋白极化靶向的分子过程知之甚少。最近，正端定向运动肌球蛋白Va被证明在跨膜蛋白靶向树突中起关键作用；然而，肌球蛋白马达在轴突靶向中的作用尚不清楚。在这里，我们发现Myosin VI是一种负端定向马达，在轴突表面蛋白质的富集中起着至关重要的作用。工程非神经元蛋白与肌球蛋白VI相互作用，使它们在分离的大鼠皮质神经元轴突表面高度集中。此外，肌球蛋白VI功能或表达的破坏会导致轴突蛋白的异常树突定位。肌球蛋白VI至少部分通过刺激树突特异性内吞作用介导轴突表面蛋白质的富集，这一机制已被证明是许多轴突蛋白定位的基础。此外，一种与Myosin VI结合的通道视紫红质2在小鼠体内皮层神经元轴突表面集中，表明它可能是探测电路结构和功能的有用工具。总之，我们的结果表明肌凝蛋白有助于塑造轴突和树突蛋白的极化分布。在内质网（ER）和高尔基体中合成后，神经元蛋白沿着不同的运输途径到达轴突和树突质膜。这种特殊的运输依赖于沿着微管或肌动蛋白以“正端”或“负端”方向移动的运动蛋白。尽管这些途径的分子细节尚不清楚，但最近的研究表明，正端定向肌球蛋白运动将蛋白质优先引导到树突。在这里，我们发现Myosin VI，一个负端定向马达，在轴突表面的蛋白质浓度中起作用。一些研究表明，许多轴突蛋白最初是针对这两个隔室的，并且在通过内吞作用从树突表面特异性移除后，随后在轴突表面富集。我们在这里表明，这种树突特异性内吞作用是通过与肌凝蛋白VI的相互作用促进的，而阻断肌凝蛋白VI的功能会阻止轴突蛋白从树突表面内化。我们的研究结果提出了一种模型，其中神经元蛋白在轴突或树突表面富集，这是基于肌球蛋白马达与它们相互作用的特性。
In neurons polarized trafficking of vesicle-bound membrane proteins gives rise to the distinct molecular composition and functional properties of axons and dendrites. Despite their central role in shaping neuronal form and function, surprisingly little is known about the molecular processes that mediate polarized targeting of neuronal proteins. Recently, the plus-end-directed motor Myosin Va was shown to play a critical role in targeting of transmembrane proteins to dendrites; however, the role of myosin motors in axonal targeting is unknown. Here we show that Myosin VI, a minus-end-directed motor, plays a vital role in the enrichment of proteins on the surface of axons. Engineering non-neuronal proteins to interact with Myosin VI causes them to become highly concentrated at the axonal surface in dissociated rat cortical neurons. Furthermore, disruption of either Myosin VI function or expression leads to aberrant dendritic localization of axonal proteins. Myosin VI mediates the enrichment of proteins on the axonal surface at least in part by stimulating dendrite-specific endocytosis, a mechanism that has been shown to underlie the localization of many axonal proteins. In addition, a version of Channelrhodopsin 2 that was engineered to bind to Myosin VI is concentrated at the surface of the axon of cortical neurons in mice in vivo, suggesting that it could be a useful tool for probing circuit structure and function. Together, our results indicate that myosins help shape the polarized distributions of both axonal and dendritic proteins. Following synthesis in the endoplasmic reticulum (ER) and Golgi apparatus, neuronal proteins follow divergent trafficking pathways to the axonal and dendritic plasma membranes. This specialized trafficking depends on motor proteins that move along microtubules or actin in either a “plus-end” or “minus-end” direction. Although the molecular details of these pathways are poorly understood, recent work suggests that a plus-end-directed myosin motor guides proteins preferentially to dendrites. Here we find that Myosin VI, a minus-end-directed motor, plays a role in the concentration of proteins at the surface of the axon. Several studies have shown that many axonal proteins are targeted to both compartments initially, and are subsequently enriched on the axonal surface after they have been specifically removed from the surface of the dendrites by endocytosis. We show here that this dendrite-specific endocytosis is promoted by interaction with Myosin VI, whereas blocking Myosin VI function prevents axonal protein from being internalized from the surface of dendrites. Our results suggest a model where neuronal proteins are enriched on the surface of either axons or dendrites based on the properties of the myosin motor with which they interact.
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影响因子：
25
作者：
Lewis, Tommy L., Jr.;Mao, Tianyi;Svoboda, Karel;Arnold, Don B.
通讯作者：
Arnold, Don B.
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
16.2
作者：
Jacobson, C;Schnapp, B;Banker, GA
通讯作者：
Banker, GA
影响因子：
9.2
作者：
Kapitein, Lukas C.;Schlager, Max A.;Hoogenraad, Casper C.
通讯作者：
Hoogenraad, Casper C.
影响因子：
16.2
作者：
Horton, AC;Rácz, B;Ehlers, MD
通讯作者：
Ehlers, MD