Roles of Nedd4.1/2 in the auditory portion of mouse inner ear

The development of the inner ear requires close coordination between numerous cellular
processes such as proliferation, migration and differentiation. These processes depend on
transcriptional programs and post-translational modifications that must be coordinated with
precision in time and space. Ubiquitination is a reversible modification involved in the
degradation, localization, and activity of proteins, which plays a crucial role during
development. The enzymes at the center of the ubiquitination mechanism are the E3 ligases
that control substrate specificity. Among the more than 700 E3 ligases identified, we have
focused our research on Nedd4.1 and Nedd4.2 since mutations of the gene coding for
NEDD4.2 are responsible for deafness in humans. In order to understand the functions of
Nedd4.1/2 during the development of the inner ear, we first determined their expression
profile. Our in situ hybridization results indicate that these ligases are expressed throughout
the cochlear epithelium as well as in the spiral ganglion as early as the 14th embryonic day.
After birth, the expression of Nedd4.1 persists but that of Nedd4.2 decreases sharply. Our
immunohistochemistry analyses suggest that Nedd4.1/2 are localized at the intercellular
junctions of the otic epithelium and that they are enriched at the tricellular junctions. We
analyzed the integrity of the cochlear epithelium in mice invalidated for the Nedd4.2 gene
within the inner ear. Our data suggests that Nedd4.2 contributes to the establishment of
planar cell polarity since the orientation of the hair cells and their hair bundle is disrupted in
conditional mutants. Our research emphasizes the importance of Nedd4.1/2 ligases during
the development of the auditory portion of the inner ear.