Pervasive translational regulation of the cell signalling circuitry underlies mammalian development.
Pervasive translational regulation of the cell signalling circuitry underlies mammalian development.
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DOI：
10.1038/ncomms14443
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发表时间：
2017-02-14
影响因子：
16.6
通讯作者：
Barna M
中科院分区：
文献类型：
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作者：
Fujii K;Shi Z;Zhulyn O;Denans N;Barna M
哺乳动物发育过程中翻译调控的程度和动态仍知之甚少。在此，我们在体内监测了细胞特化并组织成组织时哺乳动物基因组的翻译情况。这发现了大多数核心信号通路（包括Shh、Wnt、Hippo、PI3K和MAPK通路）存在意想不到且普遍的翻译调控。我们进一步鉴定了关键信号成分5′ - 非翻译区（UTRs）中上游开放阅读框（uORFs）的复杂情况，并对其功能进行了表征。以Shh通路为重点，我们证明了主要的SHH受体Ptch1内的uORFs在控制细胞信号传导和神经元分化方面的重要性。最后，我们表明，数百种关键组织特异性发育过程相关的mRNA的表达主要在翻译水平而非转录水平受到调控。总之，这项工作揭示了主要信号成分和基因调控网络的一个新的翻译调控层面，它使发育中的组织间基因表达在空间上多样化。
基因表达在多个层面受到调控，包括通过蛋白质翻译的调节。在此，作者发现翻译调控使发育中的组织间基因表达多样化，并通过上游开放阅读框（uORFs）的复杂情况调控主要信号通路。
The degree and dynamics of translational control during mammalian development remain poorly understood. Here we monitored translation of the mammalian genome as cells become specified and organize into tissues in vivo. This identified unexpected and pervasive translational regulation of most of the core signalling circuitry including Shh, Wnt, Hippo, PI3K and MAPK pathways. We further identify and functionally characterize a complex landscape of upstream open reading frames (uORFs) across 5′-untranslated regions (UTRs) of key signalling components. Focusing on the Shh pathway, we demonstrate the importance of uORFs within the major SHH receptor, Ptch1, in control of cell signalling and neuronal differentiation. Finally, we show that the expression of hundreds of mRNAs underlying critical tissue-specific developmental processes is largely regulated at the translation but not transcript levels. Altogether, this work reveals a new layer of translational control to major signalling components and gene regulatory networks that diversifies gene expression spatially across developing tissues. Gene expression is regulated at several levels, including through the modulation of protein translation. Here the authors find that translation control diversifies gene expression between developing tissues and regulates major signalling pathways through a complex landscape of upstream open reading frames (uORFs).