Dynamic regulation of mRNA decay during neural development.
Dynamic regulation of mRNA decay during neural development.
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DOI：
10.1186/s13064-015-0038-6
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发表时间：
2015-04-21
影响因子：
3.6
通讯作者：
Cleary MD
中科院分区：
文献类型：
--
作者：
Burow DA;Umeh-Garcia MC;True MB;Bakhaj CD;Ardell DH;Cleary MD
基因表达模式由 mRNA 转录和衰变的速率决定。虽然已知转录可调节许多发育过程，但 mRNA 衰减的作用尚不那么广泛定义。确定 mRNA 衰减在神经发育中的作用的关键一步是测量神经组织中全基因组 mRNA 的衰减率。这些信息应该揭示 mRNA 衰减对差异基因表达的影响程度，并为识别影响神经 mRNA 衰减的调控机制提供基础。我们开发了一种技术，可以在完整的果蝇胚胎、所有组织、特别是神经系统中进行全基因组 mRNA 衰减测量。我们的方法揭示了神经特异性的衰变动力学，包括编码轴突发生调节因子的转录本的稳定以及编码核糖体蛋白和组蛋白的转录本的不稳定。我们还确定了 mRNA 稳定性与 mRNA 生理特性之间的相关性；预计在轴突生长锥或树突内翻译的 mRNA 具有较长的半衰期，而编码调节神经发生的转录因子的 mRNA 具有较短的半衰期。对候选顺式调节元件的搜索发现，编码神经发生调节剂的 mRNA 中 Pumilio 识别元件 (PRE) 富集。我们发现 RNA 结合蛋白 Pumilio 表达的减少稳定了预测的神经 mRNA 靶标，并且 PRE 对于触发神经系统中的报告基因转录衰减是必要的。我们发现，差异性 mRNA 衰减导致参与细胞命运决定、轴突发生和果蝇神经发育过程中其他关键事件的转录本的相对丰度。神经特异性衰变动力学和 mRNA 衰变的功能特异性表明存在动态神经发育 mRNA 衰变网络。我们发现 Pumilio 是该网络的一个组成部分，揭示了这种 RNA 结合蛋白的新功能。本文的在线版本 (doi:10.1186/s13064-015-0038-6) 包含补充材料，可供授权用户使用。
Gene expression patterns are determined by rates of mRNA transcription and decay. While transcription is known to regulate many developmental processes, the role of mRNA decay is less extensively defined. A critical step toward defining the role of mRNA decay in neural development is to measure genome-wide mRNA decay rates in neural tissue. Such information should reveal the degree to which mRNA decay contributes to differential gene expression and provide a foundation for identifying regulatory mechanisms that affect neural mRNA decay. We developed a technique that allows genome-wide mRNA decay measurements in intact Drosophila embryos, across all tissues and specifically in the nervous system. Our approach revealed neural-specific decay kinetics, including stabilization of transcripts encoding regulators of axonogenesis and destabilization of transcripts encoding ribosomal proteins and histones. We also identified correlations between mRNA stability and physiologic properties of mRNAs; mRNAs that are predicted to be translated within axon growth cones or dendrites have long half-lives while mRNAs encoding transcription factors that regulate neurogenesis have short half-lives. A search for candidate cis-regulatory elements identified enrichment of the Pumilio recognition element (PRE) in mRNAs encoding regulators of neurogenesis. We found that decreased expression of the RNA-binding protein Pumilio stabilized predicted neural mRNA targets and that a PRE is necessary to trigger reporter-transcript decay in the nervous system. We found that differential mRNA decay contributes to the relative abundance of transcripts involved in cell-fate decisions, axonogenesis, and other critical events during Drosophila neural development. Neural-specific decay kinetics and the functional specificity of mRNA decay suggest the existence of a dynamic neurodevelopmental mRNA decay network. We found that Pumilio is one component of this network, revealing a novel function for this RNA-binding protein. The online version of this article (doi:10.1186/s13064-015-0038-6) contains supplementary material, which is available to authorized users.
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