Functions of NEDD4-2 in the auditory portion of the inner ear

Hearing loss is the most common neurosensory disorder with more than 466 million people affected worldwide. In most cases, hearing loss is caused by the dysfunction or the loss of the sensory cells (the hair cells) and/or their afferent neurons (spiral ganglion neurons) in the cochlea. To date, many genetic mutations have been associated with congenital deafness or early-onset hearing loss, allowing for the discovery of genes involved in the development or maintenance of the cochlea. A recent report identified deafness-associated mutations in the gene encoding the E3 Ubiquitin-ligase NEDD4L in humans, we plan to uncover its implication in cochlear development and function.
We first characterized the spatio-temporal expression of NEDD4-2 by in situ hybridization, confirming the transcripts presence during the embryonic stages of cochlear development. To decipher Nedd4-2 roles during mouse cochlear development, we generated conditional knockout animals and our first results suggests an early degeneration of hair cells and their innervating spiral ganglion neurons following a gradient from the basal to the apical turn of the cochlea. This phenotype starts around P45 until P90, stage were we observed a total hair cell loss. Our results already suggest a major contribution of the ubiquitin ligase NEDD4-2 in the maintenance of the adult cochlea integrity and we will combine mouse genetics with cellular and molecular analyses to decipher the role of Nedd4-2, which may provide future therapeutic perspectives against hearing loss.