Connexin Function and Mechanisms of Cx26 Deficiency Induced Hearing Loss

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Summary Mutations of gap junction gene Cx26 (GJB2) cause the most of hereditary deafness, ranging from profound congenital deafness at birth to mild late-onset hearing loss in childhood. Mouse models show that Cx26 deficiency can induce cochlear developmental disorders, hair cell degeneration, endocochlear potential (EP) reduction, and active cochlear amplification declining. We further found that the cochlear developmental disorder rather than hair cell degeneration is a primary cause for congenital deafness, whereas late-onset hearing loss is associated with reduction of outer hair cell (OHC) electromotility even hair cells have no connexin expression. We also evidenced that K+-recycling hypothesis is not the deafness mechanism of Cx26 deficiency. However, detailed mechanisms of these pathological changes induced by Cx26 deficiency remain unclear. Moreover, little is known about pathological changes in the human cochlea. Recently, gene therapy with viral-expression of Cx26 in the cochlea was failed to restore hearing. The main reason is lack of required knowledge of Cx26 function in the cochlea and deafness mechanisms by Cx26 deficiency. In this proposal, we will continually investigate Cx26 function and cellular and molecular mechanisms of Cx26 deficiency-induced congenital deafness and late-onset hearing loss. Cx26 deficiency causes the cochlear developmental disorder, indicating that gap junction (GJ) channels as an intercellular communication conduit are crucial for the cochlear development. Many factors, such as promoters, transcription factors, and miRNAs, can regulate gene expressions during development. However, none of these regulators is permeable to GJ channels except miRNAs. miRNAs can regulate gene expression broadly and have a critical role in the organ development. Deficiency of miRNAs can cause cochlear developmental disorders. In this study, we will first test whether Cx26 deficiency can disrupt miRNA expression and intercellular communication in the cochlea to affect cochlear development in the congenital deafness. Secondly, we will define how Cx26 deficiency decline OHC electromotility leading to late-onset hearing loss, which patients are good candidates for administration of preventive and therapeutic interventions due to normal hearing in their earlier life. Recently, connexin non-channel function has been emerged. Besides forming GJ channels, connexins can participate in cell cytoskeleton formation. We will test whether Cx26 deficiency can impair cytoskeleton formation in the OHC’s supporting cells, thereby changing OHC-loading (membrane tension) and declining OHC electromotility and active cochlear amplification. Finally, we will use backward-mutation screening approach to screen Cx26 mutations in the archival human temporal bones from patients with nonsyndromic hearing loss, whose pathological changes in the cochlea have been diagnosed, to identify mutation-induced pathological changes in the human cochlea. Apparently, these studies will reveal detailed deafness mechanisms by Cx26 deficiency. Such information is urgently required for developing efficient therapies.