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
{"title":"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。","authors":"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","doi":"10.1186/s12929-025-01180-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"32 1","pages":"84"},"PeriodicalIF":12.1000,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409954/pdf/","citationCount":"0","resultStr":"{\"title\":\"Early downregulation of hair cell (HC)-specific genes in the vestibular sensory epithelium during chronic ototoxicity.\",\"authors\":\"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\",\"doi\":\"10.1186/s12929-025-01180-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":15365,\"journal\":{\"name\":\"Journal of Biomedical Science\",\"volume\":\"32 1\",\"pages\":\"84\"},\"PeriodicalIF\":12.1000,\"publicationDate\":\"2025-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409954/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biomedical Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12929-025-01180-4\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biomedical Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12929-025-01180-4","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Early downregulation of hair cell (HC)-specific genes in the vestibular sensory epithelium during chronic ototoxicity.
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.
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.