Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis

Show simple item record Nasonkin, IO en Merbs, SL en Lazo, K en Oliver, Verity en Brooks, M en Patel, K en Enke, RA en Nellissery, J en Jamrich, M en Le, YZ en Bharti, K en Fariss, RN en Rachel, RA en Zack, DJ en Rodriguez-Boulan, EJ en Swaroop, A en 2015-09-04T04:12:29Z en 2013-03-15 en
dc.identifier.citation Development, 2013, 140 (6), pp. 1330 - 1341 en
dc.identifier.issn 0950-1991 en
dc.identifier.uri en
dc.description.abstract Dysfunction or death of photoreceptors is the primary cause of vision loss in retinal and macular degenerative diseases. As photoreceptors have an intimate relationship with the retinal pigment epithelium (RPE) for exchange of macromolecules, removal of shed membrane discs and retinoid recycling, an improved understanding of the development of the photoreceptor-RPE complex will allow better design of gene- and cell-based therapies. To explore the epigenetic contribution to retinal development we generated conditional knockout alleles of DNA methyltransferase 1 (Dnmt1) in mice. Conditional Dnmt1 knockdown in early eye development mediated by Rx-Cre did not produce lamination or cell fate defects, except in cones; however, the photoreceptors completely lacked outer segments despite near normal expression of phototransduction and cilia genes. We also identified disruption of RPE morphology and polarization as early as E15.5. Defects in outer segment biogenesis were evident with Dnmt1 exon excision only in RPE, but not when excision was directed exclusively to photoreceptors. We detected a reduction in DNA methylation of LINE1 elements (a measure of global DNA methylation) in developing mutant RPE as compared with neural retina, and of Tuba3a, which exhibited dramatically increased expression in mutant retina. These results demonstrate a unique function of DNMT1-mediated DNA methylation in controlling RPE apicobasal polarity and neural retina differentiation. We also establish a model to study the epigenetic mechanisms and signaling pathways that guide the modulation of photoreceptor outer segment morphogenesis by RPE during retinal development and disease. en
dc.relation.ispartofseries Development en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.title Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis en
dc.type Journal Article en
dc.identifier.doi 10.1242/dev.086603 en
pubs.issue 6 en
pubs.begin-page 1330 en
pubs.volume 140 en
dc.identifier.pmid 23406904 en
pubs.end-page 1341 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 431087 en
dc.identifier.eissn 1477-9129 en
pubs.record-created-at-source-date 2015-09-04 en
pubs.dimensions-id 23406904 en

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