title: Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission.
abstract: Mutations in the connexin26 gene (GJB2) are the most common genetic cause of congenital bilateral non-syndromic sensorineural hearing loss. Transgenic mice were established carrying human Cx26 with the R75W mutation that was identified in a deaf family with autosomal dominant negative inheritance [Kudo T et al. (2003) Hum Mol Genet 12:995-1004]. A dominant-negative Gjb2 R75W transgenic mouse model shows incomplete development of the cochlear supporting cells, resulting in profound deafness from birth [Inoshita A et al. (2008) Neuroscience 156:1039-1047]. The Cx26 defect in the Gjb2 R75W transgenic mouse is restricted to the supporting cells; it is unclear why the auditory response is severely disturbed in spite of the presence of outer hair cells (OHCs). The present study was designed to evaluate developmental changes in the in vivo and in vitro function of the OHC, and the fine structure of the OHC and adjacent supporting cells in the R75W transgenic mouse. No detectable distortion product otoacoustic emissions were observed at any frequencies in R75W transgenic mice throughout development. A characteristic phenotype observed in these mice was the absence of the tunnel of Corti, Nuel's space, and spaces surrounding the OHC; the OHC were compressed and squeezed by the surrounding supporting cells. On the other hand, the OHC developed normally. Structural features of the lateral wall, such as the membrane-bound subsurface cisterna beneath the plasma membrane, were intact. Prestin, the voltage-dependent motor protein, was observed by immunohistochemistry in the OHC basolateral membranes of both transgenic and non-transgenic mice. No significant differences in electromotility of isolated OHCs during development was observed between transgenic and control mice. The present study indicates that normal development of the supporting cells is indispensable for proper cellular function of the OHC.
authors.affiliation: Department of Otorhinolaryngology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Minekawa
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: A
authors.initials: A
authors.lastname: Inoshita
authors.forename: T
authors.initials: T
authors.lastname: Iizuka
authors.forename: S
authors.initials: S
authors.lastname: Kakehata
authors.forename: Y
authors.initials: Y
authors.lastname: Narui
authors.forename: T
authors.initials: T
authors.lastname: Koike
authors.forename: K
authors.initials: K
authors.lastname: Kamiya
authors.forename: H-O
authors.initials: HO
authors.lastname: Okamura
authors.forename: H
authors.initials: H
authors.lastname: Shinkawa
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D002450:Cell Communication / Q000235:genetics; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D025802:Electric Capacitance; D017629:Gap Junctions / Q000378:metabolism* / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism* / Q000473:pathology; D006309:Hearing / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007760:Labyrinth Supporting Cells / Q000378:metabolism* / Q000473:pathology; D040542:Mechanotransduction, Cellular / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020409:Molecular Motor Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017711:Nonlinear Dynamics; D009925:Organ of Corti / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013016:Sound
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D020409:Molecular Motor Proteins; C498720:Pres protein, mouse; D000072259:Connexin 26