Cdh23 Gene Mutation–Induced Vestibular Dysfunction in Mice: Abnormal Stereocilia Bundle and Otolith Development and Activation of p53/FoxO Signaling Pathway

Abstract

Vestibular dysfunction (VD) is increasingly acknowledged as a significant contributor to falls and deterioration in health. Cadherin 23 (Cdh23) serves as an essential protein responsible for facilitating the mechanical transduction processes in hair cells, and variations in this gene have been recognized as possible factor to auditory impairments and VD. The gene Cdh23 encodes glycoproteins that play a role in cell adhesion and are crucial for the development of stereocilia bundles. In this research, we generated CDH23 functional null mice (Cdh23^V2J2/V2J2). Here, our findings indicated that Cdh23^V2J2/V2J2 mice exhibited weakened balance and coordination abilities, characterized by rotation and head nodding movements. The development of stereocilia and otoliths was abnormal in these mice. Scanning electron microscopy (SEM) analysis revealed abnormal changes in the arrangement and length of stereocilia bundles in Cdh23^V2J2/V2J2 mice compared to wild-type mice. The abnormal alterations of otolith shape in Cdh23^V2J2/V2J2 mice also were observed, which was smaller in saccules but larger in utricles. Furthermore, we also observed that the number of vestibular hair cells (VHCs) decreased in Cdh23^V2J2/V2J2 mice, along with significant activation of the p53 and FoxO signaling pathways at postnatal day 56 (P56). This study elucidates potential mechanisms, histopathological features, and resultant genomic alterations associated with VD in Cdh23^V2J2/V2J2 mice, thereby establishing a scientific foundation for prospective vestibular rehabilitative interventions.