Abstract
GJB2 and GJB6 are adjacent genes encoding connexin 26 (Cx26) and connexin 30 (Cx30), respectively, with overlapping expressions in the inner ear. Both genes are associated with the commonest monogenic hearing disorder, recessive isolated deafness DFNB1. Cx26 plays an important role in auditory development, while the role of Cx30 in hearing remains controversial. Previous studies found that Cx30 knockout mice had severe hearing loss along with a 90% reduction in Cx26, while another Cx30 knockout mouse model showed normal hearing with nearly half of Cx26 preserved. In this study, we used CRISPR/Cas9 technology to establish a new Cx30 knockout mouse model (Cx30−/−), which preserves approximately 70% of Cx26. We found that the 1, 3, and 6-month-old Cx30−/− mice showed mild hearing loss at full frequency. Immunofluorescence and HE staining suggested no significant differences in microstructure of the cochlea between Cx30−/− mice and wild-type mice. However, transmission electron microscopy showed slight cavity-like damage in the stria vascularis of Cx30−/− mice. And Cx30 deficiency reduced the production of endocochlear potential (EP) and the release of ATP, which may have induced hearing loss. Taken together, this study showed that lack of Cx30 can lead to hearing loss with an approximately 30% reduction of Cx26 in the present Cx30 knockout model. Hence, Cx30 may play an important rather than redundant role in hearing development.
Highlights
Hearing loss is a major global health problem, which can be caused by continued excessive noise (Guo et al, 2021), ototoxic drugs (Breglio et al, 2020), aging (Guo et al, 2021), genetic factors (Fu et al, 2021), and infections (Zhang et al, 2021), among which genetic factors caused 50% of the hearing loss
No connexin 30 (Cx30) transcript was detected in Cx30-/- mice, whereas Cx30+/- mice displayed a 57.6% reduction in expression of Cx30 mRNA compared to Cx30+/+ (WT) control mice
Compared with Wild type (WT) mice, the Auditory brainstem response (ABR) thresholds in 3-month-old Cx30-/- mice at 4, 8, 11, 16, 22, 32, and 40 kHz were elevated by 21.8 ± 2.62 (p < 0.001), 17 ± 2.9 (p < 0.001), 18.6 ± 3.4 (p < 0.001), 14.3 ± 2.9 (p < 0.001), 15 ± 4.5 (p < 0.01), and 25.5 ± 3.9 (p < 0.001) dB SPL, respectively
Summary
Hearing loss is a major global health problem, which can be caused by continued excessive noise (Guo et al, 2021), ototoxic drugs (Breglio et al, 2020), aging (Guo et al, 2021), genetic factors (Fu et al, 2021), and infections (Zhang et al, 2021), among which genetic factors caused 50% of the hearing loss. Auditory development depends on the functional maturation of cochlear hair cells (HCs) and on the normal differentiation and organization of nonsensory SCs. SCs are coupled through Cx26 and/or Cx30 GJ channels or hemichannels to form a supporting cell network, transmit ATP, ions, signals, and nutrient molecules (Bruzzone et al, 1996; Jagger and Forge, 2015; Verselis, 2019), and the microenvironment of surrounding HCs (Chen et al, 2018). ATP triggers cytosolic Ca2+ concentration oscillations and propagation of intercellular Ca2+ waves, which appear to play a crucial role in the normal development of the cochlear sensory epithelium, hearing acquisition and the functional maturation of HCs (Johnson et al, 2017; Mammano and Bortolozzi, 2018; Mazzarda et al, 2020). Chai et al (He et al, 2017; Zhang et al, 2020a,b; Zhang Y. et al, 2020) further confirmed that regenerating HCs cannot achieve functional maturity in the absence of a normal and stable microenvironment by SCs
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