Loss of Dgcr8-mediated microRNA expression in the kidney results in hydronephrosis and renal malformation.
Loss of Dgcr8-mediated microRNA expression in the kidney results in hydronephrosis and renal malformation.
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DOI：
10.1186/s12882-015-0053-1
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发表时间：
2015-04-14
期刊：
影响因子：
2.3
通讯作者：
Müller RU
中科院分区：
文献类型：
--
作者：
Bartram MP;Dafinger C;Habbig S;Benzing T;Schermer B;Müller RU
小的非编码RNA分子（miRNAs）在发育过程中调控基因表达起着关键作用。mirna在细胞水平上调控关键过程，从而影响包括肾脏形态发生在内的机体和组织发育。miRNA分子最初是作为一个较长的毛针状RNA转录物合成的，然后通过含有RNA加工酶Drosha及其基本相互作用物Dgcr8的酶复合物进行加工。产生的pre- mirna然后被Dicer切割。最近的数据显示，Dicer的缺失导致严重的发育性肾脏表型。然而，由于Dicer具有多种与miRNA无关的功能，因此尚不完全清楚所观察到的肾脏表型是否完全归因于miRNA表达的缺乏。我们利用在肾发育过程中远端肾元和输尿管芽衍生物中表达Cre重组酶的转基因小鼠系，分析了miRNAs在肾发育过程中通过条件性地缺失Dgcr8基因而发挥的作用。这些组织中Dgcr8基因缺失的动物在出生后的头两个月内出现严重的肾积水、肾囊肿、进行性肾衰竭和过早死亡，这种表型与Dicer缺失非常相似。本研究表明，发育中的肾小管系统中必需的mirna加工酶Dgcr8的条件性基因缺失会导致严重的发育缺陷和肾衰竭。这些数据证实了在Dicer敲除动物中获得的早期发现，并清楚地说明了mirna在肾脏发育中的重要作用。这些数据表明，miRNA失调可能在泌尿生殖系统先天缺陷的发病机制中起着重要但不明确的作用，并表明miRNA缺陷可能是人类疾病发展的病因。本文的在线版本（doi:10.1186/s12882-015-0053-1）包含补充材料，仅供授权用户使用。
Small non-coding RNA molecules (miRNAs) play a pivotal role in regulating gene expression in development. miRNAs regulate key processes at the cellular level and thereby influence organismal and tissue development including kidney morphogenesis. A miRNA molecule is initially synthesized as a longer hairneedle-shaped RNA transcript and then processed through an enzymatic complex that contains the RNA-processing enzyme Drosha and its essential interactor Dgcr8. Resulting pre-miRNAs are then cleaved by Dicer. Recent data showed that loss of Dicer resulted in severe developmental kidney phenotypes. However, as Dicer has multiple miRNA-independent functions, it was not entirely clear whether the observed renal phenotypes could be exclusively attributed to a lack of miRNA expression. We analyzed the role of miRNAs in kidney development by conditional gene deletion of Dgcr8 in the developing kidney using a transgenic mouse line that expresses Cre recombinase in the distal nephron and derivatives of the ureteric bud in kidney development. Animals with a gene deletion of Dgcr8 in these tissues developed severe hydronephrosis, kidney cysts, progressive renal failure and premature death within the first two months after birth, a phenotype strongly resembling Dicer deletion. Here we show that conditional gene deletion of the essential miRNA-processing enzyme Dgcr8 in the developing renal tubular system results in severe developmental defects and kidney failure. These data confirm earlier findings obtained in Dicer knock-out animals and clearly illustrate the essential role of miRNAs in kidney development. The data suggests that miRNA dysregulation may play an important, yet ill-defined role in the pathogenesis of inborn defects of the genitourinary system and indicate that miRNA defects may be causative in the development of human disease. The online version of this article (doi:10.1186/s12882-015-0053-1) contains supplementary material, which is available to authorized users.
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