title: DICER1 is essential for survival of postmitotic rod photoreceptor cells in mice.
abstract: Photoreceptor cell death is the proximal cause of blindness in many retinal degenerative disorders; hence, understanding the gene regulatory networks that promote photoreceptor survival is at the forefront of efforts to combat blindness. Down-regulation of the microRNA (miRNA)-processing enzyme DICER1 in the retinal pigmented epithelium has been implicated in geographic atrophy, an advanced form of age-related macular degeneration (AMD). However, little is known about the function of DICER1 in mature rod photoreceptor cells, another retinal cell type that is severely affected in AMD. Using a conditional-knockout (cKO) mouse model, we report that loss of DICER1 in mature postmitotic rods leads to robust retinal degeneration accompanied by loss of visual function. At 14 wk of age, cKO mice exhibit a 90% reduction in photoreceptor nuclei and a 97% reduction in visual chromophore compared with those in control littermates. Before degeneration, cKO mice do not exhibit significant defects in either phototransduction or the visual cycle, suggesting that miRNAs play a primary role in rod photoreceptor survival. Using comparative small RNA sequencing analysis, we identified rod photoreceptor miRNAs of the miR-22, miR-26, miR-30, miR-92, miR-124, and let-7 families as potential factors involved in regulating the survival of rods.
authors.affiliation: Department of Pharmacology.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sundermeier
authors.affiliation: Department of Pharmacology.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Frans
authors.initials: F
authors.lastname: Vinberg
authors.affiliation: Department of Pharmacology.
authors.forename: Debarshi
authors.initials: D
authors.lastname: Mustafi
authors.affiliation: Department of Pharmacology.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kohno
authors.affiliation: Department of Pharmacology.
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.affiliation: Center for RNA Molecular Biology, and.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Department of Ophthalmology and Visual Sciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA; and.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Kefalov
authors.affiliation: Department of Pharmacology, kxp65@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D017668:Age of Onset; D000818:Animals; D002453:Cell Cycle; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004596:Electroretinography; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D012162:Retinal Degeneration / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017423:Sequence Analysis, RNA; D041623:Tomography, Optical Coherence; D014785:Vision, Ocular
chemical_list: D005136:Eye Proteins; D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: age-related macular degeneration.; cell survival; conditional knockout; microRNA; retina