Poster (Scientific congresses and symposiums)
Roles of Nedd4-2 in the auditory portion of mouse inner ear
Pouyo, Lionel Ronald; Thelen, Nicolas; Thiry, Marc et al.
202144th Annual ARO MidWinter Virtual Meeting
 

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Keywords :
Ubiquitination; NEDD4-2; Cochlea
Abstract :
[en] Given the importance of protein ubiquitination in controlling various critical biological processes during development, together with a recent report identifying deafness-associated mutations in the human gene encoding the E3 Ubiquitin-ligase NEDD4L (Neurally Expressed and Developmentally Downregulated 4-like), we plan to uncover its implication in cochlear development and function. We first characterized the spatio-temporal expression profile of Nedd4-2, the mouse ortholog of Nedd4L, together with the closely related Nedd4-1 gene. In situ hybridization and immunohistochemistry experiments allowed us to confirm the presence of Nedd4-1 and Nedd4-2 transcripts during the embryonic stages of cochlear development. Both mRNAs are present in the sensory epithelium and the spiral ganglion. After birth, Nedd4-1 expression persists in these tissues, while Nedd4-2 transcripts were undetectable. To elucidate the role of Nedd4-2 in the inner ear, we generated conditional knockout (cKO) of Nedd4-2 in the inner ear by mating Foxg1-cre transgenic mice with Nedd4-2 Flox/flox mice. Histological analyses, Scanning Electron Microscopy, and specific immunostainings indicate that Nedd4-2 cKO cochleae develop normally during embryonic and early postnatal stages. However, similar studies performed at postnatal day 30 (P30) and later suggest an early degeneration of the hair cells and their innervating spiral ganglion neurons. Interestingly, cochlear cell loss in Nedd4-2 cKO animals follows a basal-to-apical gradient, similar to age-related or sound-induced hearing loss. Starting as early as P18, Nedd4-2 cKO are deaf, as shown by the total absence of signal in their auditory brainstem response at 90 dB. These results suggest that the severe hearing impairment impacting Nedd4-2 cKO precedes the cochlear cell loss observed around P45. Altogether, our results suggest a significant contribution of the E3 ubiquitin ligase Nedd4-2 in the developing cochlea. We are currently combining different approaches using a combination of yeast-two-hybrid, gain- and loss-of function experiments and biochemical assays to uncover the specific substrates of Nedd4-2 in the cochlea.
Research center :
Giga-Development and Stem Cells - ULiège
Disciplines :
Otolaryngology
Author, co-author :
Pouyo, Lionel Ronald ;  Université de Liège - ULiège > GIGA Stem Cells - Developmental Neurobiology
Thelen, Nicolas  ;  Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire
Thiry, Marc  ;  Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire
Nguyen, Laurent  ;  Université de Liège - ULiège > GIGA Stem Cells - Molecular Regulation of Neurogenesis
Delacroix, Laurence ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Malgrange, Brigitte  ;  Université de Liège - ULiège > Neurologie
Language :
English
Title :
Roles of Nedd4-2 in the auditory portion of mouse inner ear
Publication date :
February 2021
Event name :
44th Annual ARO MidWinter Virtual Meeting
Event organizer :
Assoiation for Research in Otolaryngology
Event date :
From 20-02-2021 to 24-02-2021
Name of the research project :
Functions of NEDD4-2 in the auditory portion of the mouse inner ear
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Fonds Léon Fredericq [BE]
Available on ORBi :
since 04 October 2021

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