Impaired Embryonic Development in Mice Overexpressing the RNA-Binding Protein TIAR
Impaired Embryonic Development in Mice Overexpressing the RNA-Binding Protein TIAR
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DOI：
10.1371/journal.pone.0011352
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发表时间：
2010-06-28
期刊：
影响因子：
3.7
通讯作者：
Morello, Dominique
中科院分区：
文献类型：
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作者：
Kharraz, Yacine;Salmand, Pierre-Adrien;Morello, Dominique
背景：TIA-1相关蛋白（TIAR）是一种穿梭的RNA结合蛋白，参与RNA代谢的多个步骤。在细胞核中，TIAR参与选择性剪接事件，而在细胞质中，TIAR作为翻译阻遏物作用于特异性转录物，例如含有富含AU元件（战神）的转录物。由于TIAR能够组装失败的起始前复合物，并聚结成称为应激颗粒的细胞质颗粒，因此TIAR也参与在暴露于环境应激的细胞中观察到的一般翻译停滞。然而，在体内的作用，这种蛋白质还没有被研究到目前为止，主要是由于严重的胚胎致死后tiar invaluation.Methodology/主要发现：要检查潜在的TIAR组织特异性在各种细胞的情况下，无论是胚胎或成人，我们构建了一个TIAR转基因等位基因（loxPGFPloxPTIAR）允许条件表达TIAR蛋白Cre重组酶活性。在这里，我们报告TIAR在小鼠胚胎发生过程中的作用。我们观察到，早期TIAR过表达导致低转基因传输与胚胎死亡率开始在早期植入后阶段。有趣的是，虽然植入前的步骤在子宫内正确地进化，但体外培养的胚胎对培养基非常敏感。对照和转基因胚胎在G2培养基中同样发育良好，而在M16培养基中培养导致eIF 2 α磷酸化，其积累在细胞质颗粒中，从而阻止转基因胚泡孵化。因此，我们的研究结果揭示了差异TIAR介导的胚胎反应人工或自然growth environment.Conclusions/Significance：本研究报告的RNA结合蛋白TIAR的紧密平衡的表达正常胚胎发育的重要性，从而强调转录后调控在早期胚胎编程的作用。
Background: TIA-1-related (TIAR) protein is a shuttling RNA-binding protein involved in several steps of RNA metabolism. While in the nucleus TIAR participates to alternative splicing events, in the cytoplasm TIAR acts as a translational repressor on specific transcripts such as those containing AU-Rich Elements (AREs). Due to its ability to assemble abortive pre-initiation complexes coalescing into cytoplasmic granules called stress granules, TIAR is also involved in the general translational arrest observed in cells exposed to environmental stress. However, the in vivo role of this protein has not been studied so far mainly due to severe embryonic lethality upon tiar invalidation.Methodology/Principal Findings: To examine potential TIAR tissue-specificity in various cellular contexts, either embryonic or adult, we constructed a TIAR transgenic allele (loxPGFPloxPTIAR) allowing the conditional expression of TIAR protein upon Cre recombinase activity. Here, we report the role of TIAR during mouse embryogenesis. We observed that early TIAR overexpression led to low transgene transmission associated with embryonic lethality starting at early post-implantation stages. Interestingly, while pre-implantation steps evolved correctly in utero, in vitro cultured embryos were very sensitive to culture medium. Control and transgenic embryos developed equally well in the G2 medium, whereas culture in M16 medium led to the phosphorylation of eIF2 alpha that accumulated in cytoplasmic granules precluding transgenic blastocyst hatching. Our results thus reveal a differential TIAR-mediated embryonic response following artificial or natural growth environment.Conclusions/Significance: This study reports the importance of the tightly balanced expression of the RNA-binding protein TIAR for normal embryonic development, thereby emphasizing the role of post-transcriptional regulations in early embryonic programming.