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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >C8ORF37 Is Required for Photoreceptor Outer Segment Disc Morphogenesis by Maintaining Outer Segment Membrane Protein Homeostasis
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C8ORF37 Is Required for Photoreceptor Outer Segment Disc Morphogenesis by Maintaining Outer Segment Membrane Protein Homeostasis

机译：通过维持外部段膜蛋白稳态，光感受器外部区段椎间盘形态发生器需要C8ORF37

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摘要

C8ORF37 is a causative gene for three different clinical forms of incurable retinal degeneration. However, the completely unknown function of C8ORF37 limits our understanding of the pathogenicity of C8ORF37 mutations. Here, we performed a comprehensive phenotypic characterization of a C8orf37 KO mouse line, generated using CRISPR/Cas9 technology. Both C8orf37 KO male and female mice exhibited progressive and simultaneous degeneration of rod and cone photoreceptors but no non-ocular phenotypes. The major ultrastructural feature of C8orf37 KO photoreceptors was massive disorganization of the outer segment (OS) membrane discs starting from the onset of disc morphogenesis during development. At the molecular level, the amounts of multiple OS-specific membrane proteins, including proteins involved in membrane disc organization, were reduced, although these proteins were targeted normally to the OS. Considering the distribution of C8ORF37 throughout the photoreceptor cell body, the normal structure of the KO photoreceptor connecting cilium, and the absence of defects in other ciliary organs of the KO mice, our findings do not support the previous notion that C8ORF37 was a ciliary protein. Because C8ORF37 is absent in the photoreceptor OS, C8ORF37 may participate in the secretory pathway of OS membrane proteins in the photoreceptor cell body and thus maintain the homeostasis of these proteins. This study established a valid animal model for future therapeutic studies of C8ORF37-associated retinal degeneration. This study also shed new light on the role of C8ORF37 in photoreceptors and on the pathogenic mechanism underlying retinal degeneration caused by C8ORF37 mutations.
机译：C8ORF37是一种致病基因，用于三种不同的视网膜变性的三种不同的临床变性。然而，C8ORF37的完全未知功能限制了我们对C8ORF37突变的致病性的理解。在这里，我们进行了使用CRISPR / CAS9技术产生的C8ORF37 KO鼠标线的全面表型表征。 C8ORF37 KO男性和雌性小鼠均表现出杆和锥形感光体的渐进和同时变性，但没有非眼部表型。 C8ORF37 KO光感受器的主要超微结构特征是从发育过程中椎间盘形态发生开始的外部区段（OS）膜盘的大规模紊乱。在分子水平中，减少了多个OS特异性膜蛋白的量，包括膜圆盘组织中涉及的蛋白质，尽管这些蛋白质通常靶向OS。考虑到整个光感受器细胞体中C8ORF37的分布，KO光感受器的正常结构连接纤毛，以及KO小鼠的其他睫状体中的缺陷，我们的发现不支持C8ORF37是睫状蛋白的前面的观念。因为C8ORF37在光感受器OS中不存在，所以C8ORF37可以参与感光细胞体中OS膜蛋白的分泌途径，从而维持这些蛋白质的稳态。本研究为C8ORF37相关视网膜变性的未来治疗研究建立了有效的动物模型。本研究还阐述了C8ORF37在光感受器中的作用以及由C8ORF37突变引起的视网膜变性的病原机制的作用。

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