The USH3A causative gene clarin1 functions in Müller glia to maintain retinal photoreceptors.

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2025-03-11 eCollection Date: 2025-03-01 DOI:10.1371/journal.pgen.1011205
Hannah J T Nonarath, Samantha L Simpson, Tricia L Slobodianuk, Hai Tran, Ross F Collery, Astra Dinculescu, Brian A Link
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引用次数: 0

Abstract

Mutations in CLRN1 cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, and often accompanied by vestibular dysfunction. The identity of the cell types responsible for the pathology and mechanisms leading to vision loss in USH3A remains elusive. To address this, we employed CRISPR/Cas9 technology to delete a large region in the coding and untranslated (UTR) region of zebrafish clrn1. The retinas of clrn1 mutant larvae exhibited sensitivity to cell stress, along with age-dependent loss of function and degeneration in the photoreceptor layer. Investigation revealed disorganization in the outer retina in clrn1 mutants, including actin-based structures of the Müller glia and photoreceptor cells. To assess cell-specific contributions to USH3A pathology, we specifically re-expressed clrn1 in either Müller glia or photoreceptor cells. Müller glia re-expression of clrn1 prevented the elevated cell death observed in larval clrn1 mutant zebrafish exposed to high-intensity light. Notably, the degree of phenotypic rescue correlated with the level of Clrn1 re-expression. Surprisingly, high levels of Clrn1 expression enhanced cell death in both wild-type and clrn1 mutant animals. However, rod- or cone-specific Clrn1 re-expression did not reduce the extent of cell death. Taken together, our findings underscore three crucial insights. First, clrn1 mutant zebrafish exhibit key pathological features of USH3A; second, Clrn1 within Müller glia plays a pivotal role in photoreceptor maintenance, with its expression requiring controlled regulation; third, the reliance of photoreceptors on Müller glia suggests a structural support mechanism, possibly through direct interactions between Müller glia and photoreceptors mediated in part by Clrn1 protein.

USH3A致病基因clarin1在 ller胶质细胞中起作用,维持视网膜光感受器。
CLRN1突变导致Usher综合征IIIA型(USH3A),这是一种常染色体隐性遗传病,以听力和视力丧失为特征,常伴有前庭功能障碍。在USH3A中负责导致视力丧失的病理和机制的细胞类型的身份仍然是难以捉摸的。为了解决这个问题,我们利用CRISPR/Cas9技术删除了斑马鱼clrn1编码和非翻译(UTR)区域的一个大区域。clrn1突变体幼虫的视网膜表现出对细胞应激的敏感性,伴随着年龄依赖性的功能丧失和感光层的退化。研究显示,clrn1突变体的外视网膜组织紊乱,包括肌动蛋白结构的神经胶质细胞和光感受器细胞。为了评估细胞特异性对USH3A病理的贡献,我们在突触神经胶质细胞或感光细胞中特异性地重新表达clrn1。在暴露于强光下的幼体clrn1突变斑马鱼中观察到,clrn1的神经胶质细胞重新表达阻止了细胞死亡的升高。值得注意的是,表型拯救的程度与Clrn1重新表达的水平相关。令人惊讶的是,高水平的Clrn1表达增加了野生型和Clrn1突变动物的细胞死亡。然而,杆状或锥状特异性Clrn1的重新表达并没有降低细胞死亡的程度。综上所述,我们的发现强调了三个关键的见解。首先,clrn1突变斑马鱼表现出USH3A的关键病理特征;其次, ller胶质细胞内的Clrn1在光感受器维持中起关键作用,其表达需要控制调控;第三,光感受器对神经状胶质细胞的依赖提示了一种结构支持机制,可能通过部分由Clrn1蛋白介导的神经状胶质细胞与光感受器之间的直接相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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