miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse Stria Vascularis

Fabiola Paciello, Anna Rita Fetoni, Giuseppe Gentile, Veronica Zorzi, Giulia Gentile, Antonio Gianmaria Spampinato, Maria Guarnaccia, Giulia Crispino, Abraham Tettey-Matey, Ferdinando Scavizzi, Sebastiano Cavallaro, Fabio Mammano

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

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.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
Numero di pagine16
RivistaFrontiers in Cell and Developmental Biology
Volume2021
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • connexins
  • early degeneration
  • hearing loss
  • molecular pathway analysis
  • oxidative stress
  • post-natal development
  • systems biology
  • vascular dysfunction

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