Kinesin-1 regulates dendrite microtubule polarity in Caenorhabditis elegans.
Kinesin-1 regulates dendrite microtubule polarity in Caenorhabditis elegans.
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作者：
Yan J;Chao DL;Toba S;Koyasako K;Yasunaga T;Hirotsune S;Shen K
在神经元中，微管(MT)跨越轴突和树突的长度，分子马达利用这些细胞内的“高速公路”将不同的货物运输到适当的亚细胞位置。轴突MTs是这样组织的，即正端从细胞体定向出来，而树突表现出混合的MTS极性，既包含负端输出的MTs，也包含正端输出的MTs。这种差异组织背后的分子机制以及它的功能意义尚不清楚。在这里，我们证明了Kinesin-1在体内建立树突特有的负端向外MT组织中起关键作用。在UNC-116(Kinesin-1/Kinesin Heavy Chain)突变体中，树突状MT采用轴突样的正端向外组织。在体外，Kinesin-1蛋白能够交联抗平行的MTS。我们认为Kinesin-1通过利用运动域和C端MT结合结构域直接将正端向外的MT滑出树突来调节树突MT的极性。DOI：http://dx.doi.org/10.7554/eLife.00133.001神经元，或神经细胞，是可兴奋的细胞，使用电信号和化学信号传递信息。神经细胞一般由一个胞体、多个树突和一个轴突组成。树突负责接收输入并将这些信号传递到细胞体，而轴突则将信号从细胞体带走并传递给其他细胞。像所有的细胞一样，神经细胞有一个由微管组成的细胞骨架，微管有助于确定细胞的形状，并充当细胞内运输的“高速公路”。微管是由交替的α和β微管蛋白组成的中空纤维：每个微管有一个‘+’端，在那里暴露β亚单位，以及一个‘负’端，在那里暴露α亚单位。神经细胞是高度极化的：在轴突内，微管均匀定向，其正端指向外部，而在树突中，有许多微管，其负端指向外部。这种安排在整个动物界都是保守的，但建立这种安排的机制在很大程度上是未知的。严等人利用模式生物秀丽线虫(线虫)对树突状微管组织进行了详细的体内分析。他们发现，一种名为Kinesin-1的运动蛋白对于在树突中产生特有的负端输出模式至关重要：当编码该蛋白质的基因被敲除时，微管中的树突经历了戏剧性的极性转变，并采用了典型的轴突的正端输出组织。突变的树突还表现出其他类似轴突的特征：例如，它们缺乏许多通常在树突中发现的蛋白质。基于这些和其他数据，严等人。提出Kinesin-1通过将正端向外的微管移出树突来决定树突中微管的极性。这些首次尝试在分子水平上解释树突状微管极性是如何在体内实现的，可能会导致对神经元细胞骨架的结构和功能的新见解。DOI：http://dx.doi.org/10.7554/eLife.00133.002
In neurons, microtubules (MTs) span the length of both axons and dendrites, and the molecular motors use these intracellular ‘highways' to transport diverse cargo to the appropriate subcellular locations. Whereas axonal MTs are organized such that the plus-end is oriented out from the cell body, dendrites exhibit a mixed MTs polarity containing both minus-end-out and plus-end-out MTs. The molecular mechanisms underlying this differential organization, as well as its functional significance, are unknown. Here, we show that kinesin-1 is critical in establishing the characteristic minus-end-out MT organization of the dendrite in vivo. In unc-116 (kinesin-1/kinesin heavy chain) mutants, the dendritic MTs adopt an axonal-like plus-end-out organization. Kinesin-1 protein is able to cross-link anti-paralleled MTs in vitro. We propose that kinesin-1 regulates the dendrite MT polarity through directly gliding the plus-end-out MTs out of the dendrite using both the motor domain and the C-terminal MT-binding domain. DOI: http://dx.doi.org/10.7554/eLife.00133.001 Neurons, or nerve cells, are excitable cells that transmit information using electrical and chemical signals. Nerve cells are generally composed of a cell body, multiple dendrites, and a single axon. The dendrites are responsible for receiving inputs and for transferring these signals to the cell body, whereas the axon carries signals away from the cell body and relays them to other cells. Like all cells, nerve cells have a cytoskeleton made up of microtubules, which help to determine cellular shape and which act as ‘highways' for intracellular transport. Microtubules are long hollow fibers composed of alternating α- and β-tubulin proteins: each microtubule has a ‘plus'-end, where the β subunits are exposed, and a ‘minus'-end, where the α subunits are exposed. Nerve cells are highly polarized: within the axon, the microtubules are uniformly oriented with their plus-ends pointing outward, whereas in dendrites, there are many microtubules with their minus-ends pointing outward. This arrangement is conserved across the animal kingdom, but the mechanisms that establish it are largely unknown. Yan et al. use the model organism Caenorhabditis elegans (the nematode worm) to conduct a detailed in vivo analysis of dendritic microtubule organization. They find that a motor protein called kinesin-1 is critical for generating the characteristic minus-end-out pattern in dendrites: when the gene that codes for this protein is knocked out, the dendrites in microtubules undergo a dramatic polarity shift and adopt the plus-end-out organization that is typical of axons. The mutant dendrites also show other axon-like features: for example, they lack many of the proteins that are usually found in dendrites. Based on these and other data, Yan et al. propose that kinesin-1 determines microtubule polarity in dendrites by moving plus-end-out microtubules out of dendrites. These first attempts to explain, at the molecular level, how dendritic microtubule polarity is achieved in vivo could lead to new insights into the structure and function of the neuronal cytoskeleton. DOI: http://dx.doi.org/10.7554/eLife.00133.002