Abstract
BackgroundMutations in GJB2, which encodes connexin 26 (Cx26), a cochlear gap junction protein, represent a major cause of pre-lingual, non-syndromic deafness. The degeneration of the organ of Corti observed in Cx26 mutant—associated deafness is thought to be a secondary pathology of hearing loss. Here we focused on abnormal development of the organ of Corti followed by degeneration including outer hair cell (OHC) loss.MethodsWe investigated the crucial factors involved in late-onset degeneration and loss of OHC by ultrastructural observation, immunohistochemistry and protein analysis in our Cx26-deficient mice (Cx26f/fP0Cre).ResultsIn ultrastructural observations of Cx26f/fP0Cre mice, OHCs changed shape irregularly, and several folds or notches were observed in the plasma membrane. Furthermore, the mutant OHCs had a flat surface compared with the characteristic wavy surface structure of OHCs of normal mice. Protein analysis revealed an increased protein level of caveolin-2 (CAV2) in Cx26f/fP0Cre mouse cochlea. In immunohistochemistry, a remarkable accumulation of CAV2 was observed in Cx26f/fP0Cre mice. In particular, this accumulation of CAV2 was mainly observed around OHCs, and furthermore this accumulation was observed around the shrunken site of OHCs with an abnormal hourglass-like shape.ConclusionsThe deformation of OHCs and the accumulation of CAV2 in the organ of Corti may play a crucial role in the progression of, or secondary OHC loss in, GJB2-associated deafness. Investigation of these molecular pathways, including those involving CAV2, may contribute to the elucidation of a new pathogenic mechanism of GJB2-associated deafness and identify effective targets for new therapies.
Highlights
Hereditary deafness is one of the most common congenital diseases. [1, 2]
In ultrastructural observations of Cx26f/fP0Cre mice, outer hair cell (OHC) changed shape irregularly, and several folds or notches were observed in the plasma membrane
This accumulation of CAV2 was mainly observed around OHCs, and this accumulation was observed around the shrunken site of OHCs with an abnormal hourglass-like shape
Summary
Hereditary deafness is one of the most common congenital diseases. [1, 2]. Approximately one in 1000 children is affected by severe hearing loss at birth or during early childhood, which is defined as pre-lingual deafness [3, 4], with approximately half of these cases attributable to genetic causes [5]. It has been reported that histopathologic evaluation of the human temporal bone in Cx26-related hearing loss revealed near-total degeneration of hair cells in the organ of Corti [9] Both a Cx26 dominant-negative model and a conditional knockout model developed secondary degeneration [10,11,12,13], which could be rescued by gene transfer with wild-type Gjb2 [14]. We demonstrate the deformation of OHCs in mice with Cx26-associated hearing loss and investigate the factors that contribute to the secondary degeneration of OHCs. Mutations in GJB2, which encodes connexin 26 (Cx26), a cochlear gap junction protein, represent a major cause of pre-lingual, non-syndromic deafness. We focused on abnormal development of the organ of Corti followed by degeneration including outer hair cell (OHC) loss
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