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首页> 外文期刊>Cytoskeleton >A cell-based screen for inhibitors of flagella-driven motility in Chlamydomonas reveals a novel modulator of ciliary length and retrograde actin flow.
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A cell-based screen for inhibitors of flagella-driven motility in Chlamydomonas reveals a novel modulator of ciliary length and retrograde actin flow.

机译：基于细胞的衣藻鞭毛驱动运动抑制剂的筛选揭示了纤毛长度和逆行肌动蛋白流量的新型调节剂。

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摘要

Cilia are motile and sensory organelles with critical roles in physiology. Ciliary defects can cause numerous human disease symptoms including polycystic kidneys, hydrocephalus, and retinal degeneration. Despite the importance of these organelles, their assembly and function is not fully understood. The unicellular green alga Chlamydomonas reinhardtii has many advantages as a model system for studies of ciliary assembly and function. Here we describe our initial efforts to build a chemical-biology toolkit to augment the genetic tools available for studying cilia in this organism, with the goal of being able to reversibly perturb ciliary function on a rapid time-scale compared to that available with traditional genetic methods. We screened a set of 5520 compounds from which we identified four candidate compounds with reproducible effects on flagella at nontoxic doses. Three of these compounds resulted in flagellar paralysis and one induced flagellar shortening in a reversible and dose-dependent fashion, accompanied by a reduction in the speed of intraflagellar transport. This latter compound also reduced the length of cilia in mammalian cells, hence we named the compound "ciliabrevin" due to its ability to shorten cilia. This compound also robustly and reversibly inhibited microtubule movement and retrograde actin flow in Drosophila S2 cells. Ciliabrevin may prove especially useful for the study of retrograde actin flow at the leading edge of cells, as it slows the retrograde flow in a tunable dose-dependent fashion until flow completely stops at high concentrations, and these effects are quickly reversed upon washout of the drug.
机译：纤毛是运动性和感觉性细胞器，在生理中起关键作用。睫状体缺陷可引起多种人类疾病症状，包括多囊肾，脑积水和视网膜变性。尽管这些细胞器很重要，但它们的组装和功能尚未完全了解。单细胞绿藻莱茵衣藻（Chlamydomonas reinhardtii）作为研究睫毛组装和功能的模型系统具有许多优势。在这里，我们描述了我们为建立化学生物学工具包而进行的最初工作，以增加可用于研究该生物中纤毛的遗传工具，其目标是与传统遗传学工具相比，能够在快速的时间范围内可逆地干扰纤毛功能。方法。我们筛选了5520种化合物，从中我们鉴定出了四种在无毒剂量下对鞭毛具有可再现作用的候选化合物。这些化合物中的三种导致鞭毛麻痹，一种导致鞭毛以可逆和剂量依赖的方式缩短，同时降低鞭毛内运输的速度。后一种化合物还减少了哺乳动物细胞中纤毛的长度，因此由于其缩短纤毛的能力，我们将其命名为“纤毛”。该化合物还强烈且可逆地抑制果蝇S2细胞中的微管运动和逆行肌动蛋白流动。纤毛蛋白可能被证明对研究细胞前缘逆行肌动蛋白的流动特别有用，因为它以可调节的剂量依赖性方式减慢了逆行肌的流动，直到高浓度下血流完全停止为止，并且在冲洗细胞后这些作用很快被逆转。药品。

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