| Summary: | <p>The function of the NEDD4 (Neuronal Cell Expressed, Developmentally Downregulated, 4) E3 Ubiquitin Ligase protein family members, NEDD4L and NEDD4, has previously been studied. However, their potential involvement in the mammalian auditory system was only recently indicated. As such, studies were undertaken to investigate the requirement of Nedd4l and Nedd4 in the process of hearing using constitutive and conditional knockout (KO) mouse models. Auditory characterisation of Nedd4l KO mice identified an early-onset hearing loss by 3-weeks of age, which progresses to profound deafness by 8-weeks of age. Pathological assessment identified fewer synapses between inner hair cells and afferent neurons in 3-week old Nedd4l KO mice, and a subsequent progressive degeneration of hair cell bundles and spiral ganglion neurons. Molecular characterisation discovered decreased abundance of αENaC subunit in Nedd4l KO mice and identified NKCC1 as a potential NEDD4L substrate, suggesting that impaired endolymphatic ion homeostasis may contribute to the auditory dysfunction in Nedd4l KO mice. In addition, auditory phenotyping indicates that Nedd4 KO mice experience a high-frequency hearing loss, which is first detected by 8-weeks of age. These studies highlight the importance of the NEDD4L and NEDD4 ubiquitin ligase proteins in supporting auditory function. However, further investigations are required to fully elaborate upon their essential roles in mammalian hearing.</p>
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