Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa.
Retinitis pigmentosa (RP) is a common hereditary eye disease that causes blindness due to a progressive loss of photoreceptors in the retina. RP can be elicited by mutations that affect the tri-snRNP subunit of the pre-mRNA splicing machinery, but how defects in this essential macromolecular complex transform into a photoreceptor-specific phenotype is unknown. We have modeled the disease in zebrafish by silencing the RP-associated splicing factor Prpf31 and observed detrimental effects on visual function and photoreceptor morphology. Despite reducing the level of a constitutive splicing factor, no general defects in gene expression were found. Instead, retinal genes were selectively affected, providing the first in vivo link between mutations in splicing factors and the RP phenotype. Silencing of Prpf4, a splicing factor hitherto unrelated to RP, evoked the same defects in vision, photoreceptor morphology and retinal gene expression. Hence, various routes affecting the tri-snRNP can elicit tissue-specific gene expression defects and lead to the RP phenotype.
Department of Biochemistry, University of Würzburg, Würzburg, Germany.
Bastian
B
Linder
Holger
H
Dill
Anja
A
Hirmer
Jan
J
Brocher
Gek Ping
GP
Lee
Sinnakaruppan
S
Mathavan
Hanno Jörn
HJ
Bolz
Christoph
C
Winkler
Bernhard
B
Laggerbauer
Utz
U
Fischer
D000818:Animals; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency / Q000235:genetics; D009154:Mutation; D009928:Organ Specificity; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics; D012160:Retina / Q000378:metabolism / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology*; D015027:Zebrafish
D005136:Eye Proteins; C555603:PRPF31 protein, mouse