Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy.
Ablation of EYS in zebrafish causes mislocalisation of outer segment proteins, F-actin disruption and cone-rod dystrophy.
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斑马鱼 EYS 的消融导致外节蛋白错误定位、F-肌动蛋白破坏和锥杆营养不良
DOI：
10.1038/srep46098
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发表时间：
2017-04-05
影响因子：
4.6
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Lu Z;Hu X;Liu F;Soares DC;Liu X;Yu S;Gao M;Han S;Qin Y;Li C;Jiang T;Luo D;Guo AY;Tang Z;Liu M
EYS的突变与常染色体隐性视网膜色素变性（arRP）和常染色体隐性视锥-视杆细胞营养不良（arCRD）相关，然而，EYS的功能以及这些突变如何导致视网膜变性的分子机制仍不清楚。由于EYS在小鼠和大鼠中不存在，并且视网膜的结构在人类和果蝇之间存在很大差异，因此我们利用斑马鱼作为模式生物来研究EYS在视网膜中的功能。我们通过TALEN技术构建了一个EYS基因敲除的斑马鱼品系，该品系在早期表现出视力障碍，而组织学和免疫荧光测定表明存在进行性视网膜变性，其中锥细胞占主导地位。这些表型概括了arCRD患者的临床表现。此外，EYS−/−斑马鱼还表现出某些外节蛋白（视紫红质，opn 1 lw，opn 1 sw 1，GNB 3和PRPH 2）的错误定位，以及光感受器中肌动蛋白丝的破坏。因此，蛋白质的错误定位可能会破坏这些斑马鱼的视锥细胞和视杆细胞的功能，并导致感光细胞死亡。总的来说，这些结果表明EYS在维持F-肌动蛋白的形态结构和蛋白质转运中的新作用，这种功能的丧失可能是最终导致感光细胞死亡的细胞事件的触发因素。
Mutations in EYS are associated with autosomal recessive retinitis pigmentosa (arRP) and autosomal recessive cone-rod dystrophy (arCRD) however, the function of EYS and the molecular mechanisms of how these mutations cause retinal degeneration are still unclear. Because EYS is absent in mouse and rat, and the structure of the retina differs substantially between humans and Drosophila, we utilised zebrafish as a model organism to study the function of EYS in the retina. We constructed an EYS-knockout zebrafish-line by TALEN technology which showed visual impairment at an early age, while the histological and immunofluorescence assays indicated the presence of progressive retinal degeneration with a cone predominately affected pattern. These phenotypes recapitulate the clinical manifestations of arCRD patients. Furthermore, the EYS−/− zebrafish also showed mislocalisation of certain outer segment proteins (rhodopsin, opn1lw, opn1sw1, GNB3 and PRPH2), and disruption of actin filaments in photoreceptors. Protein mislocalisation may, therefore, disrupt the function of cones and rods in these zebrafish and cause photoreceptor death. Collectively, these results point to a novel role for EYS in maintaining the morphological structure of F-actin and in protein transport, loss of this function might be the trigger for the resultant cellular events that ultimately lead to photoreceptor death.