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Title: | Modeling of autosomal-dominant retinitis pigmentosa in Caenorhabditis elegans uncovers a nexus between global impaired functioning of certain splicing factors and cell type-specific apoptosis |
Author: | Rubio Peña, Karinna Fontrodona, Laura Aristizábal Corrales, David Torres, Silvia Cornes, Eric García Rodríguez, Francisco J. Serrat, Xènia González-Knowles, David Foissac, Sylvain Porta de la Riva, Montserrat Cerón Madrigal, Julián |
Keywords: | Nematodes Malalties hereditàries Oftalmopaties Genetic disorders Eye diseases |
Issue Date: | Dec-2015 |
Publisher: | Cold Spring Harbor Laboratory Press |
Abstract: | Retinitis pigmentosa (RP) is a rare genetic disease that causes gradual blindness through retinal degeneration. Intriguingly, seven of the 24 genes identified as responsible for the autosomal-dominant form (adRP) are ubiquitous spliceosome components whose impairment causes disease only in the retina. The fact that these proteins are essential in all organisms hampers genetic, genomic, and physiological studies, but we addressed these difficulties by using RNAi in Caenorhabditis elegans. Our study of worm phenotypes produced by RNAi of splicing-related adRP (s-adRP) genes functionally distinguishes between components of U4 and U5 snRNP complexes, because knockdown of U5 proteins produces a stronger phenotype. RNA-seq analyses of worms where s-adRP genes were partially inactivated by RNAi, revealed mild intron retention in developing animals but not in adults, suggesting a positive correlation between intron retention and transcriptional activity. interestingly, RNAi of s-adRP genes produces an increase in the expression of atl-1 (homolog of human ATR), which is normally activated in response to replicative stress and certain DNA-damaging agents. The up-regulation of atl-1 correlates with the ectopic expression of the pro-apoptotic gene egl-1 and apoptosis in hypodermal cells, which produce the cuticle, but not in other cell types. Our model in C. elegans resembles s-adRP in two aspects: The phenotype caused by global knockdown of s-adRP genes is cell type-specific and associated with high transcriptional activity. Finally, along with a reduced production of mature transcripts, we propose a model in which the retina-specific cell death in s-adRP patients can be induced through genomic instability. |
Note: | Reproducció del document publicat a: https://doi.org/10.1261/rna.053397.115 |
It is part of: | RNA, 2015, vol. 21, num. 12, p. 2119-2131 |
URI: | http://hdl.handle.net/2445/126916 |
Related resource: | https://doi.org/10.1261/rna.053397.115 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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