Gap junction systems in the mammalian cochlea

Kikuchi, Toshihiko; Kimura, Robert S.; Paul, David L.; Takasaka, Tomonori; Adams, Joe C.

doi:10.1016/s0165-0173(99)00076-4

Cited by 236 publications

(176 citation statements)

References 8 publications

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“…2 A and B) when Cx30 is not expressed. Reduced availability of GJs may hinder the proposed K ϩ recycling (19) or intercellular diffusion of other molecules important for cellular activities and survival, ultimately resulting in the death of supporting and hair cells. Our results also imply that a 3-fold increase in Cx26 expression over the level expressed in patients with Cx30 deletion mutations could be therapeutic.…”

Section: Discussionmentioning

confidence: 99%

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Ahmad

Tang²,

Chang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

117

132

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Mutations in genes coding for connexin26 (Cx26) and/or Cx30 are linked to approximately half of all cases of human autosomal nonsyndromic prelingual deafness. Cx26 and Cx30 are the two major Cx isoforms found in the cochlea, and they coassemble to form hybrid (heteromeric and heterotypic) gap junctions (GJs). This molecular arrangement implies that homomeric GJs would remain in the cochlea if one of the coassembly partners were mutated resulting in null expression. We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30 ؊/؊ background. In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30 ؊/؊ mice. The results indicated that hybrid GJs consisting of Cx26 and Cx30 were not essential for normal hearing in mice and suggested that up-regulation of Cx26 or slowing down its protein degradation might be a therapeutic strategy to prevent and treat deafness caused by Cx30 mutations.gap junction ͉ hearing rescue ͉ hereditary deafness

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Section: Discussionmentioning

confidence: 99%

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Ahmad

Tang²,

Chang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

117

132

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“…The reduction of Cx26 expression among spiral ligament fibrocytes indicates the lack of a gap junction pathway for recycling of K + ions from perilymph to the stria vascularis. The principal site of K + uptake from perilymph is though to be type II fibrocytes (Kikuchi et al 1995;Kikuchi et al 2000). Unlike strial marginal cells, which take up K + basolaterally and expel it through their apical membranes, type II fibrocytes are not epithelial and have no apical membrane through which to expel ions.…”

Section: Role Of Tbx1 and Brn4 In Human Diseasementioning

confidence: 99%

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Braunstein

Crenshaw

Morrow

et al. 2008

JARO

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The T-box transcription factor TBX1 has been identified as the major gene responsible for the etiology of velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS). Conductive hearing loss occurs in a majority of patients with this syndrome, while sensorineural deafness has also been reported in some cases. Mutations in POU3F4/BRN4, a POU domain transcription factor, cause DFN3, an X-linked nonsyndromic form of deafness characterized by mixed conductive and sensorineural hearing loss. Inactivation of the murine orthologues of these genes causes similar defects to those seen in humans and has provided excellent models for the study of inner ear development. Tbx1 and Brn4 are expressed in the mesenchymal cells surrounding the otic vesicle and have been shown to play roles in cochlear outgrowth. Furthermore, expression of Brn4 is reduced in Tbx1 null mutants, suggesting a possible genetic interaction between these genes. To test whether Tbx1 and Brn4 function in a common pathway, mice mutant for both genes were generated and analyzed for inner ear defects. Brn4−;Tbx1+/− mutants displayed a significant reduction in the number of turns of the cochlea compared to Brn4− or Tbx1+/− mice. In addition, Brn4−;Tbx1+/− mice displayed structural defects in the apical cochlea indicative of Mondini dysplasia found in patients with either VCFS/DGS or DFN3. These data establish a genetic interaction between Tbx1 and Brn4 relevant to human disease and indicate a function of these genes in signaling from the periotic mesenchyme to the otic vesicle to direct proper coiling of the cochlear duct.

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“…12 Recent studies suggested that intercellular communication through GJ is crucial for auditory function. 13,14 In mice, Cx26 and Cx30, apparently the two most abundantly expressed Cxs, are known to co-assemble to form GJ in the cochlea. 15 Mutations of GJB2, which encodes the Cx26 protein, and GJB6, which encodes the Cx30 protein, are implicated in cases of inherited nonsyndromic hearing loss.…”

Section: Introductionmentioning

confidence: 99%

Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30

Su¹,

et al. 2010

Eur J Hum Genet

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Hearing impairment is the most common sensory disorder worldwide. In a recent study, the authors have shown that a heterozygous missense mutation, p.R184Q, in the connexin 26 (Cx26) is causally related to hearing loss. However, the functional change in the Cx26R184Q mutant remains unknown. This study compared the intracellular distribution and assembly of mutant Cx26R184Q with that of the wild-type (WT) Cx26 and Cx30WT in tet-on HeLa cells and the effect that the mutant protein had on those cells. Fluorescent localization assay of WT Cx26 showed the typical punctuate pattern of gap junction channel between neighboring expression cells. Conversely, the p.R184Q missense mutation resulted in accumulation of the Cx26 mutant protein in the Golgi apparatus rather than in the cytoplasmic membrane. Cx26R184Q coexpressed with either Cx26WT or Cx30WT showed perinuclear localization by bidirectional tet-on expression system, suggesting the impairment of the ability of both WT proteins to intracellular trafficking and targeting to the plasma membrane. Therefore, we proposed that Cx26R184Q has a dominant-negative effect on the function of WT Cx26 and Cx30.

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Gap junction systems in the mammalian cochlea

Cited by 236 publications

References 8 publications

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Cooperative Function of Tbx1 and Brn4 in the Periotic Mesenchyme is Necessary for Cochlea Formation

Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30

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