MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

被引:29
|
作者
Sundermeier, Thomas R. [1 ]
Sakami, Sanae [1 ]
Sahu, Bhubanananda [2 ]
Howell, Scott J. [2 ]
Gao, Songqi [1 ]
Dong, Zhiqian [4 ]
Golczak, Marcin [1 ,3 ]
Maeda, Akiko [2 ]
Palczewski, Krzysztof [1 ,3 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Cleveland Ctr Membrane & Struct Biol, Cleveland, OH 44106 USA
[4] Polgenix Inc, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
eye; retina; retinal degeneration; retinal metabolism; vision; ret; retina metabolism; MACULAR DEGENERATION; NLRP3; INFLAMMASOME; ALU RNA; TRANSCRIPTION FACTOR; GENE-EXPRESSION; MOUSE MODEL; C-ELEGANS; MIRNAS; ROD; PHOTORECEPTORS;
D O I
10.1074/jbc.M116.770024
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Age-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or wet form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent dry form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE). This loss results in the accumulation of toxic transcripts of Alu transposable elements, which activate the NLRP3 inflammasome and additional downstream pathways that compromise the integrity and function of the RPE. However, it remains unclear whether the loss of miRNA processing and subsequent gene regulation in the RPE due to DICER1 deficiency also contributes to RPE cell death. To clarify the role of miRNAs in RPE cells, we used two different mature RPE cell-specific Cre recombinase drivers to inactivate either Dicer1 or DiGeorge syndrome critical region 8 (Dgcr8), thus removing RPE miRNA regulatory activity in mice by disrupting two independent and essential steps of miRNA biogenesis. In contrast with prior studies, we found that the loss of each factor independently led to strikingly similar defects in the survival and function of the RPE and retina. These results suggest that the loss of miRNAs also contributes to RPE cell death and loss of visual function and could affect the pathology of dry AMD.
引用
收藏
页码:3366 / 3378
页数:13
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