Function of C8ORF37 in Photoreceptors

项目摘要 视杆细胞和视锥细胞分别是负责暗光视觉和日光色觉的感光器。这个 视杆和视锥的外节(OS)是一种扩大的纤毛，用于光传导，含有许多紧密的纤毛。 排列好的膜片。在发育过程中，OS蛋白在内段合成，并 被输送到连接纤毛的远端。这些OS蛋白随后对 含有组织良好的膜盘的OSS的形态发生。此过程中的缺陷与 各种遗传性视网膜退行性疾病。我们研究的长期目标是理解 通过研究遗传性视网膜相关基因探讨OS视盘形态发生的机制 堕落的人。摘要视网膜色素变性是最常见的遗传性视网膜变性。 每4000人中就有1人。这种疾病影响杆状细胞和随后的圆锥体。视锥-杆状营养不良(CRD)是另一种 一种遗传性视网膜变性，患病率为40,000人中有1人，影响视锥细胞或同时影响两者 圆锥体和杆状细胞同时存在。C8ORF37基因是早发性RP和CRD的致病基因。 该基因编码的蛋白质不属于任何蛋白质家族，也不具有任何已知的结构域。 功能。通过CRISPR/Cas9技术已经产生了几个携带C8orf37突变的小鼠株系 在我们的实验室里。发现OS膜结构紊乱的这些突变小鼠的表型特征 视盘和几种OS膜蛋白在OS形态发生过程中的还原。基于这些 观察到，本研究的中心假设是C8ORF37在光感受器OS盘中起作用 通过参与一组OS膜蛋白的折叠、降解和/或运输来实现形态发生 杆状和圆锥状都有。为了验证这一假设，将进行两个具体目标。在具体目标1中，主要目标是 C8orf37基因敲除小鼠OS膜蛋白减少的原因将在两种情况下进行研究 杆状和圆锥状。将专门研究蛋白质折叠、运输和/或降解方面的潜在缺陷。 在具体目标2中，C8ORF37功能的分子机制将通过研究 C8ORF37功能域的革命性保守及其相互作用蛋白的鉴定 这项研究的完成将为光感受器的OS盘形态发生提供新的见解，并可能 有利于C8ORF37突变引起的RP和CRD的临床研究。

Project Summary Rods and cones are photoreceptors responsible for dim light vision and day light color vision, respectively. The outer segment (OS) of rods and cones is an enlarged cilium for phototransduction containing many tightly- aligned membrane discs. During development, the OS proteins are synthesized in the inner segment and transported to the distal end of the connecting cilium. These OS proteins subsequently contribute to the morphogenesis of OSs containing well-organized membrane discs. Defects in this process are associated with various inherited retinal degenerative diseases. The long-term goal of our research is to understand the mechanism underlying OS disc morphogenesis through investigating genes associated with inherited retinal degenerations. Retinitis pigmentosa (RP) is the most common inherited retinal degeneration with a prevalence of 1 in 4,000 people. This disease affects rods and subsequently cones. Cone-rod dystrophy (CRD) is another form of inherited retinal degenerations with a prevalence of 1 in 40,000 people, affecting either cones or both cones and rods simultaneously. C8ORF37 was identified as a causative gene for early onset RP and CRD. This gene encodes a protein that does not belong to any protein families or possess any domains of known functions. Several mouse lines carrying C8orf37 mutations have been generated by CRISPR/Cas9 technology in our laboratory. Phenotypic characterization of these mutant mice found disorganization of OS membrane discs and reduction of several OS membrane proteins during OS morphogenesis. Based on these observations, the central hypothesis of this study is that C8ORF37 functions in photoreceptor OS disc morphogenesis by participating in folding, degradation and/or transport of a group of OS membrane proteins in both rods and cones. To test this hypothesis, two specific aims will be conducted. In specific aim 1, the primary cause underlying the decrease of OS membrane proteins in C8orf37 knockout mice will be investigated in both rods and cones. Potential defects in protein folding, transport and/or degradation will be specifically examined. In specific aim 2, the molecular mechanism underlying C8ORF37 function will be addressed by studying the revolutionarily conserved functional domain of C8ORF37 and identifying C8ORF37-interacting proteins. Completion of this study will provide new insights into OS disc morphogenesis in photoreceptors and may benefit clinical research on RP and CRD caused by C8ORF37 mutations.