Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa
Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa
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DOI：
10.1093/hmg/ddq473
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发表时间：
2011-01-15
影响因子：
3.5
通讯作者：
Fischer, Utz
中科院分区：
文献类型：
--
作者：
Linder, Bastian;Dill, Holger;Fischer, Utz
视网膜色素变性（RP）是一种常见的遗传性眼病，由于视网膜中光感受器的进行性丧失而导致失明。RP可以引起的突变，影响前体mRNA剪接机制的三-snRNP亚基，但如何在这一重要的大分子复合物的缺陷转化为光受体特异性表型是未知的。我们通过沉默RP相关剪接因子Prpf 31在斑马鱼中模拟了这种疾病，并观察到对视觉功能和感光细胞形态的不利影响。尽管减少了组成性剪接因子的水平，但没有发现基因表达的一般缺陷，相反，视网膜基因被选择性地影响，提供了剪接因子突变和RP表型之间的第一个体内联系。Prpf 4是一种迄今为止与RP无关的剪接因子，沉默Prpf 4引起了视觉、感光细胞形态和视网膜基因表达的相同缺陷。因此，影响三-snRNP的各种途径可以引起组织特异性基因表达缺陷并导致RP表型。
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.