title: Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing.
abstract: Mutations in the Gjb2 gene, which encodes a gap junction protein connexin26 (Cx26), are the most prevalent form of hereditary deafness in humans and represent about half of non-syndromic congenital deafness cases in many ethnic populations. Cochlear potassium (K+) recycling in mature cochlea is required for normal hearing. It is thought that gap junctions are essential for K+ recycling and that Gjb2 mutations cause Gjb2-associated deafness by disrupting K+ recycling in mature cochlea. Here we present evidence showing that Gjb2 is required for normal development of the neonatal organ of Corti prior to the onset of the hearing in mice. In the conditional Gjb2 null (cCx26 null) mice, ribbon synapses in inner hair cells remained poorly developed, the afferent type I fibers failed to finish the refinement process to form convergent innervation to individual inner hair cells. The spontaneous depolarizing activities in the supporting cells, which normally diminish in the wild type cochleae after postnatal day 8 (P8), remained strong in the cochlea after P8 in the mutant mice. Furthermore, the deafness phenotype was readily generated only if the Cx26 expression in the organ of Corti was significantly reduced before P6. Similar amount of Cx26 reduction in more mature cochleae had a much weaker effect in damaging the hearing sensitivity. Our findings indicated that Cx26 plays essential roles in the maturation process of the organ of Corti prior to the establishment of high K+ in the endolymph and the onset of hearing. These results suggest that successful treatment of Cx26 deafness requires early intervention before the cochlea fully matures.
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.
authors.forename: Wenxue
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.
authors.forename: Yeunjung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA; Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D056970:Co-Repressor Proteins; D003051:Cochlea / Q000166:cytology* / Q000254:growth & development*; D000072259:Connexin 26; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005697:Galactosides / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism / Q000648:ultrastructure; D006309:Hearing / Q000235:genetics*; D007211:Indoles / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010750:Phosphoproteins; D018091:Receptors, AMPA / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D056970:Co-Repressor Proteins; D017630:Connexins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; C000607042:GJB2 protein, human; D005697:Galactosides; C000607043:Gjb2 protein, mouse; D007211:Indoles; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D018091:Receptors, AMPA; D000072259:Connexin 26; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
keywords: Connexin26 function; Deafness; Development; Gjb2 mutation; Potassium recycle