Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear

Reduced phosphatidylinositol 4,5-bisphosphate synthesis impairs inner ear Ca 2+ signaling and high-frequency hearing acquisition

“…Indeed, we have shown previously that genetic manipulation of these connexins strongly affects Ca 2+ signal generation and propagation (17,21,27). The present results single out Cx26 and Cx30 as both targets and effectors of Ca 2+ signaling in the developing cochlea.…”

“…Note that normal auditory thresholds were reported for adult Cx30 +/− mice (30), whereas both Cx30 −/− mice (21, 30) and mice with targeted ablation of Cx26 in the inner ear (31,32) are profoundly deaf at all tested frequencies. We also showed that whole-cochlea samples from postnatal Cx30 −/− mice have only ∼8% residual Cx26 mRNA (27). Here we found significantly reduced levels (P < 0.001) of Cx26 (58% ± 8%) and Cx30 (54% ± 9%) in the cochlea of (n = 4) P5 Cx30 +/− mice compared with (n = 4) age-matched WT controls.…”

“…The corresponding figures for Cx30 mRNA were 70% ± 5%, 79% ± 5%, and 67% ± 4% in the apical, middle, and basal turn, respectively. Thus, impaired IP 3 R Ca 2+ signaling in cochlear nonsensory cells due to PIPKIγ deficiency causes significant downregulation of both connexin transcripts (P < 0.005), whereas our prior work determined that deletion of either Cx26 or Cx30 impairs IP 3 R Ca 2+ signaling in cochlear nonsensory cells (17,27). A seemingly logical conclusion is that IP 3 R Ca 2+ signaling establishes a tight feedback loop between channel function and transcript levels of Cx26 and Cx30 in the developing cochlea.…”

“…Our prior work with cochlear organotypic cultures had noted that [Ca 2+ ] i oscillations in nonsensory cells participate in the coordinated regulation of connexin26 (Cx26) and connexin30 (Cx30) expression through the nuclear factor-κ light chain enhancer of activated B cells (NF-κB) (27), a thoroughly investigated Ca 2+ -dependent transcription factor (22,23,28). These are the only connexins expressed in the organ of Corti nonsensory cells (29), and they are essential for the cell-to-cell propagation of Ca 2+ signals (14,17,18).…”

Persistence and transmission of recessive deafness and sign language: new insights from village sign languages

“…6 The close proximity of the GJB2 and GJB6 genes within the genome, and the co-ordinated regulation of their expression in the inner ear, means that DFNB1 deafness can be considered in many respects as a single, monogenic recessive disorder. 9,10 Nance et al 5 compared different US national surveys on deafby-deaf marriages to corroborate the hypothesis that the frequency of DFNB1 deafness among the US population has substantially increased over the last two centuries, 4 in parallel with the spread of sign language schools. The schooling presumably would have allowed a better integration of deaf people within a broader deaf community, favoring homogamy and higher marriage and reproductive rates, finally increasing genetic fitness.…”