Early downregulation of hair cell (HC)-specific genes in the vestibular sensory epithelium during chronic ototoxicity.

IF 12.1 2区 医学 Q1 CELL BIOLOGY
Mireia Borrajo, Erin A Greguske, Alberto F Maroto, Aïda Palou, Ana Renner, Víctor Giménez-Esbrí, David Sedano, Marta Gut, Anna Esteve-Codina, Beatriz Martín-Mur, Alejandro Barrallo-Gimeno, Jordi Llorens
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引用次数: 0

Abstract

Background: Exposure of mammals to ototoxic compounds causes hair cell (HC) loss in the vestibular sensory epithelia of the inner ear. In chronic exposure models, this loss often occurs by extrusion of the HC from the sensory epithelium towards the luminal cavity. HC extrusion is preceded by several steps that begin with detachment and synaptic uncoupling of the cells from the afferent terminals of their postsynaptic vestibular ganglion neurons. The purpose of this study was to identify gene expression mechanisms that drive these responses to chronic ototoxic stress.

Methods: We conducted four RNA-seq experiments that generated five comparisons of control versus treated animals. These involved two species (rat and mouse), two compounds (streptomycin and 3,3'-iminodipropionitrile, IDPN), and three time points in our rat/IDPN model. We compared differentially expressed genes and their associated Gene Ontology terms, and several genes of interest were validated by in-situ hybridisation and immunofluorescence analyses.

Results: Common and model-unique expression responses were identified. The earliest and most robust common response was downregulation of HC-specific genes, including stereocilium (Atp2b2, Xirp2), synaptic (Nsg2), and ion channel genes (Kcnab1, Kcna10), together with new potential biomarkers of HC stress (Vsig10l2). A second common response across species and compounds was the upregulation of the stress mediator Atf3. Model- or time-restricted responses included downregulation of cell-cell adhesion and mitochondrial ATP synthesis genes, and upregulation of the interferon response, unfolded protein response, and tRNA aminoacylation genes.

Conclusions: The present results provide key information on the responses of the vestibular sensory epithelium to chronic ototoxic stress, potentially relevant to other types of chronic stress.

慢性耳毒性过程中前庭感觉上皮毛细胞特异性基因的早期下调。
背景:哺乳动物暴露于耳毒性化合物会导致内耳前庭感觉上皮的毛细胞(HC)丢失。在慢性暴露模型中,这种损失通常是由于HC从感觉上皮向管腔挤压而发生的。HC挤压发生前有几个步骤,从细胞与突触后前庭神经节神经元的传入端分离和突触解耦开始。本研究的目的是确定驱动这些慢性耳毒性应激反应的基因表达机制。方法:我们进行了四次RNA-seq实验,产生了对照和治疗动物的五次比较。这些研究涉及两个物种(大鼠和小鼠),两种化合物(链霉素和3,3'-亚氨基二丙腈,IDPN),以及我们的大鼠/IDPN模型中的三个时间点。我们比较了差异表达基因及其相关的基因本体术语,并通过原位杂交和免疫荧光分析验证了一些感兴趣的基因。结果:确定了常见和模型特有的表达反应。最早和最强烈的常见反应是HC特异性基因的下调,包括体纤毛(Atp2b2, Xirp2),突触(Nsg2)和离子通道基因(Kcnab1, Kcna10),以及新的HC应激潜在生物标志物(Vsig10l2)。跨物种和化合物的第二个共同反应是应激介质Atf3的上调。模型或时间限制反应包括下调细胞-细胞粘附和线粒体ATP合成基因,上调干扰素反应、未折叠蛋白反应和tRNA氨基酰化基因。结论:目前的结果提供了前庭感觉上皮对慢性耳毒性应激反应的关键信息,可能与其他类型的慢性应激有关。
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
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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