Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos.
Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos.
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DOI：
10.1371/journal.pgen.0020134
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发表时间：
2006-08-25
期刊：
影响因子：
4.5
通讯作者：
Müller HA
中科院分区：
文献类型：
--
作者：
Meyer WJ;Schreiber S;Guo Y;Volkmann T;Welte MA;Müller HA
Argonaute蛋白是驱动RNA沉默的分子机制的重要组成部分。在果蝇中，Argonaute蛋白家族的不同成员被分配到不同的RNA沉默途径。虽然Ago 1是microRNA功能所必需的，但Ago 2是siRNA触发的RNA干扰中RNA诱导沉默复合物的关键组分。果蝇Ago 2含有一个不寻常的氨基末端，具有两种功能未知的不完美的富含谷氨酰胺的重复序列（GRR）。在这里，我们表明，GRR的Ago 2蛋白的正常功能是必不可少的。GRR数量减少的等位基因导致与中囊胚过渡相关的两个形态发生过程的特定中断：膜生长和基于微管的细胞器运输。这些缺陷似乎不是由于干扰siRNA依赖性过程，而是表明干扰Ago 1依赖性途径中的突变Ago 2蛋白。使用功能丧失的等位基因，我们进一步证明，Ago 1和Ago 2的行为在一个部分冗余的方式来控制表达的片段极性基因wingless在早期胚胎。我们的研究结果反对Ago 1和Ago 2功能的严格分离，并表明这些蛋白质协同作用，以控制中囊胚过渡和节段性模式的关键步骤。细胞采用不同的机制来控制其基因的活性，在过去的十年中，发现了一种称为RNA沉默的基因调控新策略。负责RNA沉默的中心组分是Argonaute蛋白。虽然Argonaute蛋白的许多分子特性已经被发现，但对它们在生物体中的功能知之甚少。在果蝇中，令人困惑的是，单个Argonaute蛋白的突变导致发育中令人惊讶的轻微缺陷，尽管RNA沉默已被认为在基因调控中起主要作用。Meyer和同事描述了果蝇中Argonaute家族的两个成员Ago 1和Ago 2以冗余的方式发挥作用。以前，这两种蛋白质被证明介导不同的RNA沉默途径。作者表明，在早期胚胎中，Ago 1和Ago 2在两个基本过程中共同发挥作用：通过控制蛋白质和细胞器的不均匀分布来产生细胞内的极性，以及通过调节重要的细胞-细胞信号通路来产生组织的极性。这些结果将Argonaute蛋白的活性以及RNA沉默机制与细胞和发育生物学的中心问题（即细胞和组织中极性的调节）联系起来。
Argonaute proteins are essential components of the molecular machinery that drives RNA silencing. In Drosophila, different members of the Argonaute family of proteins have been assigned to distinct RNA silencing pathways. While Ago1 is required for microRNA function, Ago2 is a crucial component of the RNA-induced silencing complex in siRNA-triggered RNA interference. Drosophila Ago2 contains an unusual amino-terminus with two types of imperfect glutamine-rich repeats (GRRs) of unknown function. Here we show that the GRRs of Ago2 are essential for the normal function of the protein. Alleles with reduced numbers of GRRs cause specific disruptions in two morphogenetic processes associated with the midblastula transition: membrane growth and microtubule-based organelle transport. These defects do not appear to result from disruption of siRNA-dependent processes but rather suggest an interference of the mutant Ago2 proteins in an Ago1-dependent pathway. Using loss-of-function alleles, we further demonstrate that Ago1 and Ago2 act in a partially redundant manner to control the expression of the segment-polarity gene wingless in the early embryo. Our findings argue against a strict separation of Ago1 and Ago2 functions and suggest that these proteins act in concert to control key steps of the midblastula transition and of segmental patterning. Cells employ diverse mechanisms to control the activity of their genes, and over the last ten years, a new strategy for gene regulation called RNA silencing has been discovered. Central components responsible for RNA silencing are Argonaute proteins. While many of the molecular properties of Argonaute proteins have been uncovered, little is known about their function in living organisms. In Drosophila, it has been puzzling that mutations in individual Argonaute proteins lead to surprisingly mild defects in development, although RNA silencing had been suggested to play major roles in gene regulation. Meyer and coworkers describe that Ago1 and Ago2, two Argonaute family members in Drosophila, function in a redundant fashion. Previously, these two proteins were demonstrated to mediate distinct pathways of RNA silencing. The authors show that in early embryos Ago1 and Ago2 work together in two fundamental processes: the generation of polarity within cells, by controlling the unequal distributions of proteins and cell organelles, and the polarity of tissues, by modulating an important cell-cell signaling pathway. These results connect the activity of Argonaute proteins and by extension the mechanisms of RNA silencing with central problems of cell and developmental biology, namely the regulation of polarity in cells and tissues.
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