Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina
Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina
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DOI：
10.1523/jneurosci.0828-08.2008
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发表时间：
2008-05-07
影响因子：
5.3
通讯作者：
Strettoi, Enrica
中科院分区：
文献类型：
--
作者：
Damiani, Devid;Alexander, John J.;Strettoi, Enrica
microRNA（miRNAs）是一类高度保守的小分子，通过与特定的靶mRNA结合来调控基因的表达。Dicer是一种RNase III内切核酸酶，对于成熟miRNA的产生和功能至关重要，并且Dicer的去除已被证明会破坏许多发育过程。在这项研究中，使用floxed Dicer条件等位基因和视网膜Chx10Cre转基因从视网膜特异性去除Dicer。视网膜Dicer基因敲除小鼠表现出可再现的对光反应的无能。此外，在出生后第16天观察到光感受器视网膜形成的形态缺陷，随着动物年龄的增长，其进展为更普遍的细胞解体和视网膜细胞类型的广泛变性。这伴随着暗视和明视视网膜电图（ERG）反应的降低。有趣的是，去除单个Dicer等位基因会导致整个生命过程中的ERG缺陷，但不会导致形态异常。Dicer缺失视网膜的北方印迹分析显示几种miRNA减少。在去除Dicer后发生进行性视网膜变性的观察结果提出了miRNA参与视网膜神经变性疾病的可能性。
MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs, and removal of Dicer has been shown to disrupt many developmental processes. In this study, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knock-out mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at postnatal day 16, which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic electroretinogram ( ERG) responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer-depleted retinas showed a decrease in several miRNAs. The observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders.