An essential role for maternal control of Nodal signaling.
An essential role for maternal control of Nodal signaling.
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DOI：
10.7554/elife.00683
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发表时间：
2013-09-10
期刊：
影响因子：
7.7
通讯作者：
Sampath K
中科院分区：
文献类型：
--
作者：
Kumari P;Gilligan PC;Lim S;Tran LD;Winkler S;Philp R;Sampath K
生长因子信号传导对于干细胞多能性的模式形成、生长、分化和维持是必不可少的。从海胆到哺乳动物，轴的形成和胚层的特化都需要与节点相关的信号因子。斑马鱼Nodal因子的母体转录本Squint（Sqt）定位于未来的胚胎背侧。母体sqt/nodal RNA定位和调节的机制尚不清楚。在这里，我们表明，通过保守的Y盒结合蛋白1（Ybx1）的Nodal信号的母体控制是必不可少的。我们通过蛋白质组学筛选鉴定了Ybx1。Ybx1识别sqt RNA的3 '非翻译区（UTR），并防止过早翻译和Sqt/Nodal信号传导。斑马鱼ybx1的母体效应突变导致Nodal信号失调、原肠胚形成失败和胚胎死亡。植入的Nodal包被珠表型复制ybx1突变缺陷。因此，Ybx1阻止异位Nodal活性，揭示了Nodal信号调节的新范式，这可能是保守的。DOI：www.example.com在许多生物体中，胚胎发育部分是由RNA控制的，RNA在母亲体内形成时沉积在卵子中。这些“母体RNA”可能定位于卵子或胚胎的特定区域，然后专门翻译成蛋白质并执行其特定功能。这有助于在发育中的有机体中建立不对称性，也就是说，产生最终将成为有机体的顶部或底部，前部或后部，左侧或右侧的组织。一种这样的母体RNA编码Nodal，一种在脊椎动物和一些无脊椎动物生物体中保守的关键信号分子。在斑马鱼中，与之相当的RNA被称为斜视，在胚胎发育中起着重要作用。由母体沉积的斜视RNA定位于背部区域--胚胎的背部--并向该区域发出信号以形成背部组织，但斜视是如何被调节的还不清楚。现在，Kumari等人确定了一种控制斜视RNA定位的蛋白质，并发现它也可以阻止这种RNA被翻译成蛋白质。斜视RNA含有一个"背侧定位元件"，该元件在4细胞阶段将其招募到胚胎的背侧细胞（即，在卵子受精后的两次细胞分裂中）。Kumari等人发现了一种名为Ybx1的蛋白质，它可以与这种元件结合：这种蛋白质可能有助于正确定位许多其他生物体中的RNA，包括果蝇和哺乳动物。引人注目的是，当母体衍生的Ybx1蛋白发生突变时，胚胎形成异常，这些突变也阻止了斜视RNA的正确定位。这表明母体来源的Ybx 1蛋白直接调节斜视RNA。除了正确定位斜视RNA外，胚胎还必须在正确的时间将这种RNA翻译成蛋白质。在具有突变的母体Ybx1蛋白的胚胎中，可以在16细胞阶段检测到斜视蛋白，而在野生型胚胎中，该蛋白直到256细胞阶段才翻译;这表明Ybx1蛋白可能通常抑制斜视RNA的翻译。事实上，Kumari等人发现Ybx1与另一种蛋白质eIF4E结合，eIF4E将mRNA募集到核糖体（细胞的翻译机器）。因此，Ybx1可能阻止eIF4E与核糖体复合物的其他成分结合，并启动斜视RNA的翻译，直到接收到额外的信号。确定这种调节机制在其他生物体中有多普遍将是有趣的。DOI：www.example.com网站
Growth factor signaling is essential for pattern formation, growth, differentiation, and maintenance of stem cell pluripotency. Nodal-related signaling factors are required for axis formation and germ layer specification from sea urchins to mammals. Maternal transcripts of the zebrafish Nodal factor, Squint (Sqt), are localized to future embryonic dorsal. The mechanisms by which maternal sqt/nodal RNA is localized and regulated have been unclear. Here, we show that maternal control of Nodal signaling via the conserved Y box-binding protein 1 (Ybx1) is essential. We identified Ybx1 via a proteomic screen. Ybx1 recognizes the 3’ untranslated region (UTR) of sqt RNA and prevents premature translation and Sqt/Nodal signaling. Maternal-effect mutations in zebrafish ybx1 lead to deregulated Nodal signaling, gastrulation failure, and embryonic lethality. Implanted Nodal-coated beads phenocopy ybx1 mutant defects. Thus, Ybx1 prevents ectopic Nodal activity, revealing a new paradigm in the regulation of Nodal signaling, which is likely to be conserved. DOI: http://dx.doi.org/10.7554/eLife.00683.001 In many organisms, embryonic development is controlled in part by RNAs that are deposited into the egg as it forms inside the mother. These ‘maternal RNAs’ may localize to particular regions of the egg or embryo, where they are then exclusively translated into protein and carry out their specific function. This helps to establish asymmetry in the developing organism—that is, to produce tissues that will eventually become the top or bottom, front or back, and left or right of the organism. One such maternal RNA encodes Nodal, a key signaling molecule that is conserved across vertebrate and some invertebrate organisms. In zebrafish, the equivalent RNA is called squint, and plays an important role in embryonic development. The squint RNA deposited by the mother localizes to the dorsal region—the embryo’s back—and signals that region to make dorsal tissues, but how squint is regulated is not well understood. Now, Kumari et al. identify a protein that controls the positioning of squint RNA, and find that it can also prevent this RNA from being translated into protein. The squint RNA contains a ‘dorsal localization element’ that recruits it to the dorsal cells of the embryo by the 4-cell stage (i.e., within two cell divisions after the egg is fertilized). Kumari et al. identified a protein called Ybx1 that could bind to this element: this protein may help to correctly position RNAs in many other organisms, including fruit flies and mammals. Strikingly, embryos formed abnormally when their maternally derived Ybx1 protein was mutant, and these mutations also prevented the squint RNA from localizing properly. This suggests that maternally derived Ybx1 protein directly regulates the squint RNA. As well as positioning the squint RNA correctly, the embryo must translate this RNA into protein at the right time. In embryos with mutant maternal Ybx1 protein, the Squint protein could be detected at the 16-cell stage, whereas in wild-type embryos this protein is not translated until the 256-cell stage; this indicates that Ybx1 protein might normally repress the translation of the squint RNA. Indeed, Kumari et al. found that Ybx1 binds to another protein—eIF4E—that recruits mRNAs to the ribosome (the cell’s translational machinery). Ybx1 might therefore prevent eIF4E from associating with other components of the ribosomal complex, and initiating the translation of the squint RNA, until additional signals have been received. It will be interesting to determine how widespread this regulatory mechanism is in other organisms. DOI: http://dx.doi.org/10.7554/eLife.00683.002