microRNA-138 modulates cardiac patterning during embryonic development
microRNA-138 modulates cardiac patterning during embryonic development
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DOI：
10.1073/pnas.0804673105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Srivastava, Deepak
中科院分区：
文献类型：
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作者：
Morton, Sarah U.;Scherz, Paul J.;Srivastava, Deepak
胚胎发育过程中的器官模式需要精确的时间和空间调节蛋白质活性。microRNAs （miRNAs）是一种通常抑制蛋白质表达的小非编码rna，对正常发育非常重要，但它们在器官发生过程中的个体功能在很大程度上是未知的。我们报道miR-138在斑马鱼心脏的特定区域表达，并且需要建立适当的腔室特异性基因表达模式。miR-138功能的破坏导致通常局限于房室瓣膜区域的基因表达的心室扩张，最终导致心室心肌细胞形态和心功能的破坏。拮抗剂对miR-138的时间特异性敲低表明，在受精后24-34小时（hpf）的离散发育窗口中，miR-138的功能是必需的。miR-138通过抑制脑室中维甲酸合成酶醛脱氢酶-1a2发挥部分功能。这种活性由mir -138介导的对编码versican （cspg2）基因的心室抑制补充，该基因受到视黄酸信号传导的正调节。我们的研究结果表明，miR-138通过靶向共同途径的多个成员，有助于在心脏形态发生过程中建立离散的基因表达域，并且还建立了在鱼类中使用拮抗剂来暂时敲低miRNA功能。
Organ patterning during embryonic development requires precise temporal and spatial regulation of protein activity. microRNAs (miRNAs), small noncoding RNAs that typically inhibit protein expression, are broadly important for proper development, but their individual functions during organogenesis are largely unknown. We report that miR-138 is expressed in specific domains in the zebrafish heart and is required to establish appropriate chamber-specific gene expression patterns. Disruption of miR-138 function led to ventricular expansion of gene expression normally restricted to the atrio-ventricular valve region and, ultimately, to disrupted ventricular cardiomyocyte morphology and cardiac function. Temporal-specific knockdown of miR-138 by antagomiRs showed miR-138 function was required during a discrete developmental window, 24-34 h post-fertilization (hpf). miR-138 functioned partially by repressing the retinoic acid synthesis enzyme, aldehyde dehydrogenase-1a2, in the ventricle. This activity was complemented by miR-138-mediated ventricular repression of the gene encoding versican (cspg2), which was positively regulated by retinoic-acid signaling. Our findings demonstrate that miR-138 helps establish discrete domains of gene expression during cardiac morphogenesis by targeting multiple members of a common pathway, and also establish the use of antagomiRs in fish for temporal knockdown of miRNA function.