title: MicroRNAs are essential for differentiation of the retinal pigmented epithelium and maturation of adjacent photoreceptors.
abstract: Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many protein-coding genes are known to be expressed in RPE and are important for its development and maintenance, virtually nothing is known about the in vivo roles of non-coding transcripts. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and a few were implicated to play role in RPE based on studies in cell lines. Here, through RPE-specific conditional mutagenesis of Dicer1 or Dgcr8 in mice, the importance of miRNAs for RPE differentiation was uncovered. miRNAs were found to be dispensable for maintaining RPE fate and survival, and yet they are essential for the acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly, miRNAs of the RPE are required for maturation of adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The alterations in the miRNA and mRNA profiles in the Dicer1-deficient RPE point to a key role of miR-204 in regulation of the RPE differentiation program in vivo and uncover the importance of additional novel RPE miRNAs. This study reveals the combined regulatory activity of miRNAs that is required for RPE differentiation and for the development of the adjacent neuroretina.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Ohana
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weiman-Kelman
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Shaul
authors.initials: S
authors.lastname: Raviv
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
authors.affiliation: Bioinformatics Unit, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Rinon
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Dvir
authors.initials: D
authors.lastname: Netanely
authors.affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.affiliation: The Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Arie S
authors.initials: AS
authors.lastname: Solomon
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel ruthash@post.tau.ac.il.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010786:Photoreceptor Cells / Q000378:metabolism; D010858:Pigmentation; D012160:Retina / Q000196:embryology* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D012243:Rhodopsin / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D059467:Transcriptome
chemical_list: C574692:MIRN204 microRNA, mouse; D035683:MicroRNAs; C577982:Mirn211 microRNA, mouse; D012243:Rhodopsin; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Dgcr8; Dicer1; Eye development; MicroRNA; Mouse; Photoreceptor; RPE