Deletion of the transmembrane protein Prom1b in zebrafish disrupts outer-segment morphogenesis and causes photoreceptor degeneration
Deletion of the transmembrane protein Prom1b in zebrafish disrupts outer-segment morphogenesis and causes photoreceptor degeneration
复制标题
斑马鱼跨膜蛋白 Prom1b 的缺失会破坏外节形态发生并导致光感受器变性
DOI：
10.1074/jbc.ra119.008618
复制
发表时间：
2019-09-20
影响因子：
4.8
通讯作者：
Liu, Mugen
中科院分区：
文献类型：
--
作者：
Lu, Zhaojing;Hu, Xuebin;Liu, Mugen
人类突出蛋白1 （PROM1）编码一种主要定位于质膜突出的跨膜糖蛋白，据报道其突变可导致视网膜色素变性、黄斑变性和锥杆营养不良。虽然PROM1在敲除PROM1小鼠外段（OS）形态发生中的结构作用已被证实，但这些复杂疾病表型的机制尚不清楚。在这里，我们利用斑马鱼模型来进一步研究PROM1在视网膜中的作用。斑马鱼中Prom1的同源基因包括prom1a和prom1b，我们的研究结果表明，在斑马鱼的光感受器中发挥重要作用的是prom1b，而不是prom1a。prom1b的缺失破坏了OS的形态发生，杆状体和锥体表现出不同的损伤：锥体在早期退化，而杆状体仍然存活，但OS异常，甚至在受精后9个月。对WT斑马鱼的免疫荧光实验显示，Prph2是人类跨膜蛋白peripherin 2的同源物，也与OS的形成有关，定位于OS的边缘，并且在锥形OS中的表达比在杆状OS中的表达更高。此外，我们发现Prom1b的缺失会导致Prph2的错误定位并破坏其寡聚化。我们得出结论，视锥细胞和视杆细胞之间Prph2水平的差异是导致这些视网膜结构中PROM1突变诱导的不同表型的原因之一。这些发现扩大了我们对PROM1突变引起的表型的理解，并为其功能提供了重要的见解。
Mutations in human prominin 1 (PROM1), encoding a transmembrane glycoprotein localized mainly to plasma membrane protrusions, have been reported to cause retinitis pigmentosa, macular degeneration, and cone-rod dystrophy. Although the structural role of PROM1 in outer-segment (OS) morphogenesis has been demonstrated in Prom1-knockout mouse, the mechanisms underlying these complex disease phenotypes remain unclear. Here, we utilized a zebrafish model to further investigate PROM1's role in the retina. The Prom1 orthologs in zebrafish include prom1a and prom1b, and our results showed that prom1b, rather than prom1a, plays an important role in zebrafish photoreceptors. Loss of prom1b disrupted OS morphogenesis, with rods and cones exhibiting differences in impairment: cones degenerated at an early age, whereas rods remained viable but with an abnormal OS, even at 9 months postfertilization. Immunofluorescence experiments with WT zebrafish revealed that Prph2, an ortholog of the human transmembrane protein peripherin 2 and also associated with OS formation, is localized to the edge of OS and is more highly expressed in the cone OS than in the rod OS. Moreover, we found that Prom1b deletion causes mislocalization of Prph2 and disrupts its oligomerization. We conclude that the variation in Prph2 levels between cones and rods was one of the reasons for the different PROM1 mutation-induced phenotypes of these retinal structures. These findings expand our understanding of the phenotypes caused by PROM1 mutations and provide critical insights into its function.