title: MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice.
abstract: 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 ofAlutransposable 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-specificCrerecombinase drivers to inactivate eitherDicer1or 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.
authors.affiliation: Departments of Pharmacology.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sundermeier
authors.affiliation: Departments of Pharmacology.
authors.forename: Sanae
authors.initials: S
authors.lastname: Sakami
authors.affiliation: Ophthalmology and Visual Sciences, School of Medicine.
authors.forename: Bhubanananda
authors.initials: B
authors.lastname: Sahu
authors.affiliation: Ophthalmology and Visual Sciences, School of Medicine.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Howell
authors.affiliation: Departments of Pharmacology.
authors.forename: Songqi
authors.initials: S
authors.lastname: Gao
authors.affiliation: Polgenix, Inc., Cleveland, Ohio 44106.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Departments of Pharmacology; Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.affiliation: Ophthalmology and Visual Sciences, School of Medicine.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Departments of Pharmacology; Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: kxp65@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D000818:Animals; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012160:Retina; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*
chemical_list: C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: eye; ret; retina; retina metabolism; retinal degeneration; retinal metabolism; vision