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.
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.
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Karinna
K
Rubio-Peña
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Laura
L
Fontrodona
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
David
D
Aristizábal-Corrales
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Silvia
S
Torres
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Eric
E
Cornes
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Francisco J
FJ
García-Rodríguez
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Xènia
X
Serrat
Integromics, Integromics SL, Parque Científico de Madrid, 28760, Tres Cantos, Madrid, Spain.
David
D
González-Knowles
INRA, GenPhySE, F-31326 Castanet-Tolosan, France.
Sylvain
S
Foissac
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain C. elegans Core Facility, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Montserrat
M
Porta-De-La-Riva
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain.
Julián
J
Cerón
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D005799:Genes, Dominant; D009928:Organ Specificity; D034622:RNA Interference; D012326:RNA Splicing; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000235:genetics; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; C112486:EGL-1 protein, C elegans; D012097:Repressor Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D017415:Ribonucleoprotein, U5 Small Nuclear; C576885:Atl-1 protein, C elegans; D064007:Ataxia Telangiectasia Mutated Proteins
C. elegans; RNA-seq; intron retention; retinitis pigmentosa; spliceosome