A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status.
A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status.
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DOI：
10.1038/ncomms8576
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发表时间：
2015-07-06
影响因子：
16.6
通讯作者：
Makeyev EV
中科院分区：
文献类型：
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作者：
Dai W;Li W;Hoque M;Li Z;Tian B;Makeyev EV
神经系统(NS)的发育依赖于以精确的时空方式对广泛的基因集进行协调上调。如何在分子水平上协调这种转录组范围的影响仍然是一个悬而未决的问题。在这里，我们发现多个神经转录本的3‘-非翻译区(3’-UTRs)含有由Tristetraprolin(TTP/Zfp36)识别的富含AU的顺式元件(Ares)，Tristetraprolin(TTP/Zfp36)是一种RNA结合蛋白，先前参与了mRNA稳定性的调节。我们进一步证明，由于NS丰富的microRNA miR-9介导的TTP蛋白表达减少，神经谱系中ARE依赖的mRNA降解效率下降。重要的是，在这种情况下，TTP的下调对于适当的神经元分化是必不可少的。另一方面，TTP在非神经细胞中的失活会导致多种NS特异性基因的显著上调。我们的结论是，新发现的miR-9/TTP电路限制了非神经元细胞中神经元mRNAs的意外积累，并确保了这些转录产物在神经元中的协同上调。神经系统的发育依赖于广泛的基因以精确的时空方式一致上调。在这里，作者表明miR-9/TTP电路确保神经元中神经元mRNAs的协调上调，并限制这些转录物在非神经元细胞中的计划外积累。
Nervous system (NS) development relies on coherent upregulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3′-untranslated regions (3′ UTRs) of multiple neural transcripts contain AU-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously implicated in regulation of mRNA stability. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines in the neural lineage because of a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Importantly, TTP downregulation in this context is essential for proper neuronal differentiation. On the other hand, inactivation of TTP in non-neuronal cells leads to dramatic upregulation of multiple NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated upregulation of these transcripts in neurons. Nervous system development relies on coherent up-regulation of extensive genes in a precise spatiotemporal manner. Here, the authors show that miR-9/TTP circuitry ensures coordinated up-regulation of neuronal mRNAs in neurons and limits unscheduled accumulation of these transcripts in non-neuronal cells.