Developmental abnormalities in supporting cell phalangeal processes and cytoskeleton in the GJB2 knockdown mouse model

Abstract

Mutations in the GJB2 gene (which encodes Connexin26 (Cx26)) are the most common causes of hereditary hearing loss, and previous studies showed postnatal development arrest of the organ of Corti in different Cx26-null mouse models. To further explore the pathological changes and the mechanism behind the cochlear abnormalities in these mice, we established transgenic mouse models by conditional knockdown of cochlear Cx26 at postnatal day (P) 0 and P8. Auditory brainstem responses were recorded and the morphological features in the organ of Corti were analyzed 18 days later after Cx26 knockdown in the different groups of mice. The mice in the P0 knockdown group displayed severe hearing loss at all frequencies, while the mice in the P8 knockdown group showed nearly normal hearing. The organ of Corti displayed normal architecture and no ultrastructural changes was observed in the P8 knockdown group. However, the phalangeal processes of Deiter's cells did not develop into finger-like structures, and the formation of microtubules in the pillar cells was significantly reduced in the P0 knockdown group. Moreover, the amount of acetylated α-tubulin was reduced in pillar cells in the P0 knockdown group. Our results indicate that the GJB2 gene participates in the postnatal development of the cytoskeleton in pillar cells during the structural maturation of the organ of Corti. The microtubule reduction in pillar cells might be responsible for the failure of the tunnel of Corti to open in P0 knockdown mice, and the malformed phalangeal processes in the P0 knockdown mice might negatively affect the supporting framework of the organ of Corti, which would be a novel mechanism of GJB2-related hearing loss.