Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein.
Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein.
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DOI：
10.1371/journal.pone.0142836
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zarnescu DC
中科院分区：
文献类型：
--
作者：
Novak SM;Joardar A;Gregorio CC;Zarnescu DC
RNA结合蛋白在转录后基因表达调控中起着关键作用，但对它们在心脏功能中的作用知之甚少。RNA结合蛋白的脆性X（FraX）家族最常在神经系统疾病的背景下进行研究，因为脆性X智力低下1（FMR 1）的突变是遗传性智力低下的主要原因。最近，脆性X相关蛋白1（FXR 1）水平的改变，脊椎动物横纹肌中表达的主要FraX成员，已与小鼠和斑马鱼模型中的结构和功能缺陷有关。FraX蛋白是已确立的翻译调节剂，并且已知其调节不同组织中的特异性靶标。为了破译FraX蛋白在体内心脏中的直接作用，我们转向果蝇，它拥有一个唯一的，功能保守的和普遍表达的FraX蛋白，dFmr1。使用经典的功能等位基因丢失以及肌肉特异性RNAi敲低，我们表明果蝇FMRP，dFmr1，是发育过程中适当心率所必需的。在通过RNAi敲低心脏特异性dFmr1的背景下的功能分析表明，dFmr1在心脏细胞中自主地调节心率是细胞所需的。有趣的是，这些功能缺陷并不伴随着任何明显的结构异常，这表明dFmr1可能调控果蝇中的靶点与脊椎动物不同。综上所述，我们的研究结果支持了dFmr1蛋白对心脏功能至关重要的假设，并建立了果蝇作为研究FraX蛋白在心脏中作用的新模型。
RNA binding proteins play a pivotal role in post-transcriptional gene expression regulation, however little is understood about their role in cardiac function. The Fragile X (FraX) family of RNA binding proteins is most commonly studied in the context of neurological disorders, as mutations in Fragile X Mental Retardation 1 (FMR1) are the leading cause of inherited mental retardation. More recently, alterations in the levels of Fragile X Related 1 protein, FXR1, the predominant FraX member expressed in vertebrate striated muscle, have been linked to structural and functional defects in mice and zebrafish models. FraX proteins are established regulators of translation and are known to regulate specific targets in different tissues. To decipher the direct role of FraX proteins in the heart in vivo, we turned to Drosophila, which harbors a sole, functionally conserved and ubiquitously expressed FraX protein, dFmr1. Using classical loss of function alleles as well as muscle specific RNAi knockdown, we show that Drosophila FMRP, dFmr1, is required for proper heart rate during development. Functional analyses in the context of cardiac-specific dFmr1 knockdown by RNAi demonstrate that dFmr1 is required cell autonomously in cardiac cells for regulating heart rate. Interestingly, these functional defects are not accompanied by any obvious structural abnormalities, suggesting that dFmr1 may regulate a different repertoire of targets in Drosophila than in vertebrates. Taken together, our findings support the hypothesis that dFmr1 protein is essential for proper cardiac function and establish the fly as a new model for studying the role(s) of FraX proteins in the heart.