Gene expression pattern of NEDD4-1/2 in the developing inner ear

Protein ubiquitination is an important post-translational modification that is involved in multiple cellular processes such as protein degradation, endocytosis, sorting, trafficking and turnover. A recently identified mutation in human NEDD4L gene, which encodes the E3 ubiquitin-ligase NEDD4-2, has been shown to lead to several abnormalities in patients such as cerebral atrophy, optic atrophy, and hearing impairment. This observation, combined with the fact that NEDD4-2 knockout mice are deaf lead us to investigate the roles of NEDD4-1/2 in the development of the inner ear. The first part of the project focuses on establishing the expression pattern of Nedd4-1/2 mRNAs and proteins in the inner ear by in situ hybridization and immunohistofluorescence, respectively. We show that both NEDD4-1 and NEDD4-2 are dynamically expressed in the embryonic cochlea, with transcripts present in the mechanosensory hair cells, the greater epithelium ridge, spiral ganglion neurons and the stria vascularis. We notice that while NEDD4-1 expression remains in these structures at postnatal stages, NEDD4-2 expression is significantly reduced. This NEDD4-2 expression profile suggest a role of NEDD4-2 in cochlear cell proliferation, differentiation and patterning. Functional and histological studies are ongoing on NEDD4-2 knockout animals in order to decipher its role on hearing and cochlear development.