Connexin-mediated signaling in nonsensory cells is crucial for the development of sensory inner hair cells in the mouse cochlea

摘要

Mutations in the genes encoding for gap junction proteins connexin 26 (Cx26) and connexin 30 (Cx30) have been linked to syndromic and\udnonsyndromic hearing loss in mice and humans. The release of ATP from connexin hemichannels in cochlear nonsensory cells has been\udproposed to be the main trigger for action potential activity in immature sensory inner hair cells (IHCs), which is crucial for the\udrefinement of the developing auditory circuitry. Using connexin knock-out mice, we show that IHCs fire spontaneous action potentials\udeven in the absence of ATP-dependent intercellular Ca 2 signaling in the nonsensory cells. However, this signaling from nonsensory cells\udwas able to increase the intrinsic IHC firing frequency. We also found that connexin expression is key to IHC functional maturation. In\udCx26 conditional knock-out mice (Cx26Sox10-Cre), the maturation of IHCs, which normally occurs at approximately postnatal day 12, was\udpartially prevented. Although Cx30 has been shown not to be required for hearing in young adult mice, IHCs from Cx30 knock-out mice\udexhibited a comprehensive brake in their development, such that their basolateral membrane currents and synaptic machinery retain a\udprehearing phenotype. We propose that IHC functional differentiation into mature sensory receptors is initiated in the prehearing\udcochlea provided that the expression of either connexin reaches a threshold level. As such, connexins regulate one of the most crucial\udfunctional refinements in the mammalian cochlea, the disruption of which contributes to the deafness phenotype observed in mice and\udDFNB1 patients.