Reduced postnatal expression of cochlear Connexin26 induces hearing loss and affects the developmental status of pillar cells in a dose-dependent manner

Mutations in the GJB2 gene (which encodes Connexin26 (Cx26)) are the most common cause of non-syndromic deafness. Previous studies showed that an extensive knockout of the Gjb2 gene in cochlear epithelium can cause severe deafness, significant hair cell (HC) loss and failure of pillar cells (a type of supporting cell, PCs) to differentiate in mice. This study aimed to establish different mouse models with gradient reductions of cochlear Cx26 expression and to investigate the effect of different reduced levels of cochlear Cx26 expression on hearing and development of PCs. According to the reduction in the levels of cochlear Cx26, these models were named high knockdown (KD), middle KD and low KD group. In the low KD group, the mice showed normal hearing and well-developed PCs. In the high KD group, up to 90 percent of supporting cells (SCs) lost Cx26 expression. These mice exhibited severe deafness, rapid hair cell degeneration and juvenile PCs. In the middle KD group, nearly half of SCs lost Cx26 expression. However, these mice showed a moderate deafness and a late-onset hair cell loss. Moreover, nearly all the PCs in mice of this group were in a partially differentiated state. These results indicated that reduction of postnatal expression of cochlear Cx26 induces hearing loss in a dose-dependent manner. Null Cx26 in a few SCs affects the developmental status of PCs and the hair cell degeneration pattern. The abnormal developmental status of PCs may be a potential cause of Gjb2-related hearing loss.