miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis
Pathogenic mutations in the non-syndromic hearing loss and deafness 1 (DFNB1) locus are the primary cause of monogenic inheritance for prelingual hearing loss. To unravel molecular pathways involved in etiopathology and look for early degeneration biomarkers, we used a system biology approach to ana...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2021-01-01
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Series: | Frontiers in Cell and Developmental Biology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2020.616878/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giulia Gentile Fabiola Paciello Fabiola Paciello Veronica Zorzi Veronica Zorzi Antonio Gianmaria Spampinato Antonio Gianmaria Spampinato Maria Guarnaccia Giulia Crispino Abraham Tettey-Matey Ferdinando Scavizzi Marcello Raspa Anna Rita Fetoni Anna Rita Fetoni Sebastiano Cavallaro Fabio Mammano Fabio Mammano |
spellingShingle |
Giulia Gentile Fabiola Paciello Fabiola Paciello Veronica Zorzi Veronica Zorzi Antonio Gianmaria Spampinato Antonio Gianmaria Spampinato Maria Guarnaccia Giulia Crispino Abraham Tettey-Matey Ferdinando Scavizzi Marcello Raspa Anna Rita Fetoni Anna Rita Fetoni Sebastiano Cavallaro Fabio Mammano Fabio Mammano miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis Frontiers in Cell and Developmental Biology connexins molecular pathway analysis early degeneration systems biology hearing loss vascular dysfunction |
author_facet |
Giulia Gentile Fabiola Paciello Fabiola Paciello Veronica Zorzi Veronica Zorzi Antonio Gianmaria Spampinato Antonio Gianmaria Spampinato Maria Guarnaccia Giulia Crispino Abraham Tettey-Matey Ferdinando Scavizzi Marcello Raspa Anna Rita Fetoni Anna Rita Fetoni Sebastiano Cavallaro Fabio Mammano Fabio Mammano |
author_sort |
Giulia Gentile |
title |
miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis |
title_short |
miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis |
title_full |
miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis |
title_fullStr |
miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis |
title_full_unstemmed |
miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis |
title_sort |
mirna and mrna profiling links connexin deficiency to deafness via early oxidative damage in the mouse stria vascularis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-01-01 |
description |
Pathogenic mutations in the non-syndromic hearing loss and deafness 1 (DFNB1) locus are the primary cause of monogenic inheritance for prelingual hearing loss. To unravel molecular pathways involved in etiopathology and look for early degeneration biomarkers, we used a system biology approach to analyze Cx30−/− mice at an early cochlear post-natal developmental stage. These mice are a DFNB1 mouse model with severely reduced expression levels of two connexins in the inner ear, Cx30, and Cx26. Integrated analysis of miRNA and mRNA expression profiles in the cochleae of Cx30−/− mice at post-natal day 5 revealed the overexpression of five miRNAs (miR-34c, miR-29b, miR-29c, miR-141, and miR-181a) linked to apoptosis, oxidative stress, and cochlear degeneration, which have Sirt1 as a common target of transcriptional and/or post-transcriptional regulation. In young adult Cx30−/− mice (3 months of age), these alterations culminated with blood barrier disruption in the Stria vascularis (SV), which is known to have the highest aerobic metabolic rate of all cochlear structures and whose microvascular alterations contribute to age-related degeneration and progressive decline of auditory function. Our experimental validation of selected targets links hearing acquisition failure in Cx30−/− mice, early oxidative stress, and metabolic dysregulation to the activation of the Sirt1–p53 axis. This is the first integrated analysis of miRNA and mRNA in the cochlea of the Cx30−/− mouse model, providing evidence that connexin downregulation determines a miRNA-mediated response which leads to chronic exhaustion of cochlear antioxidant defense mechanisms and consequent SV dysfunction. Our analyses support the notion that connexin dysfunction intervenes early on during development, causing vascular damage later on in life. This study identifies also early miRNA-mediated biomarkers of hearing impairment, either inherited or age related. |
topic |
connexins molecular pathway analysis early degeneration systems biology hearing loss vascular dysfunction |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2020.616878/full |
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doaj-3f5c1a6757a44493910d53641e31af122021-01-25T07:46:06ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-01-01810.3389/fcell.2020.616878616878miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria VascularisGiulia Gentile0Fabiola Paciello1Fabiola Paciello2Veronica Zorzi3Veronica Zorzi4Antonio Gianmaria Spampinato5Antonio Gianmaria Spampinato6Maria Guarnaccia7Giulia Crispino8Abraham Tettey-Matey9Ferdinando Scavizzi10Marcello Raspa11Anna Rita Fetoni12Anna Rita Fetoni13Sebastiano Cavallaro14Fabio Mammano15Fabio Mammano16Department of Biomedical Sciences, National Research Council (CNR) Institute for Biomedical Research and Innovation, Catania, ItalyDepartment of Neuroscience, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyDepartment of Head and Neck Surgery, Università Cattolica del Sacro Cuore, Rome, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute of Biochemistry and Cell Biology, Rome, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute for Biomedical Research and Innovation, Catania, ItalyDepartment of Mathematics and Computer Science, University of Catania, Catania, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute for Biomedical Research and Innovation, Catania, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute of Biochemistry and Cell Biology, Rome, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute of Biochemistry and Cell Biology, Rome, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute of Biochemistry and Cell Biology, Rome, ItalyFondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyFondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyDepartment of Head and Neck Surgery, Università Cattolica del Sacro Cuore, Rome, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute for Biomedical Research and Innovation, Catania, ItalyDepartment of Biomedical Sciences, National Research Council (CNR) Institute of Biochemistry and Cell Biology, Rome, ItalyDepartment of Physics and Astronomy “G. Galilei”, University of Padua, Padua, ItalyPathogenic mutations in the non-syndromic hearing loss and deafness 1 (DFNB1) locus are the primary cause of monogenic inheritance for prelingual hearing loss. To unravel molecular pathways involved in etiopathology and look for early degeneration biomarkers, we used a system biology approach to analyze Cx30−/− mice at an early cochlear post-natal developmental stage. These mice are a DFNB1 mouse model with severely reduced expression levels of two connexins in the inner ear, Cx30, and Cx26. Integrated analysis of miRNA and mRNA expression profiles in the cochleae of Cx30−/− mice at post-natal day 5 revealed the overexpression of five miRNAs (miR-34c, miR-29b, miR-29c, miR-141, and miR-181a) linked to apoptosis, oxidative stress, and cochlear degeneration, which have Sirt1 as a common target of transcriptional and/or post-transcriptional regulation. In young adult Cx30−/− mice (3 months of age), these alterations culminated with blood barrier disruption in the Stria vascularis (SV), which is known to have the highest aerobic metabolic rate of all cochlear structures and whose microvascular alterations contribute to age-related degeneration and progressive decline of auditory function. Our experimental validation of selected targets links hearing acquisition failure in Cx30−/− mice, early oxidative stress, and metabolic dysregulation to the activation of the Sirt1–p53 axis. This is the first integrated analysis of miRNA and mRNA in the cochlea of the Cx30−/− mouse model, providing evidence that connexin downregulation determines a miRNA-mediated response which leads to chronic exhaustion of cochlear antioxidant defense mechanisms and consequent SV dysfunction. Our analyses support the notion that connexin dysfunction intervenes early on during development, causing vascular damage later on in life. This study identifies also early miRNA-mediated biomarkers of hearing impairment, either inherited or age related.https://www.frontiersin.org/articles/10.3389/fcell.2020.616878/fullconnexinsmolecular pathway analysisearly degenerationsystems biologyhearing lossvascular dysfunction |