Related Experiment Video
Updated: Jun 1, 2026
Data Acquisition and Analysis In Brainstem Evoked Response Audiometry In Mice
Published on: May 10, 2019
Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice
Nobutaka Ohgami1, Michiru Ida-Eto, Naomi Sakashita
1Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Japan.
Abstract:
c-Ret has been shown to be crucial for neural development and survival. We have recently shown that complete impairment of tyrosine 1062 (Y1062)-phosphorylation in c-Ret causes congenital hearing loss with neurodegeneration of spiral ganglion neurons (SGNs) in homozygous c-Ret knockin mice (c-Ret-KI(Y1062F/Y1062F)-mice). However, there is no information to link c-Ret and age-related hearing loss. Here we show that partial impairment of Y1062-phosphorylation in c-Ret accelerates age-related hearing loss in heterozygous c-Ret Y1062F knockin mice (c-Ret-KI(Y1062F/+)-mice). In contrast, complete impairment of serine 697 (S697)-phosphorylation in c-Ret did not affect hearing levels in 10-month-old homozygous c-Ret S697A knockin mice (c-Ret-KI(S697A/S697A)-mice). The hearing loss involved late-onset neurodegeneration of spiral ganglion neurons in c-Ret-KI(Y1062F/+)-mice. Morphological abnormalities in inner- and outer-hair cells and the stria vascularis in c-Ret-KI(Y1062F/+)-mice were undetectable. The acceleration of age-related hearing loss in c-Ret-KI(Y1062F/+)-mice was rescued by introducing constitutively activated RET. Thus, our results suggest that c-Ret is a novel age-related hearing loss-related molecule in mice. Our results suggest that these hearing losses partially share a common pathogenesis that is monogenetically caused by a single point mutation (Y1062F) in c-Ret.
Insights
Impaired c-Ret phosphorylation at tyrosine 1062 accelerates age-related hearing loss and spiral ganglion neuron degeneration in mice. This suggests c-Ret is a novel factor in age-related hearing impairment.
Area of Science:
- Neuroscience
- Genetics
- Otolaryngology
Background:
- c-Ret signaling is vital for neural development and survival.
- Complete c-Ret tyrosine 1062 (Y1062) phosphorylation impairment causes congenital hearing loss and spiral ganglion neuron (SGN) degeneration.
- The role of c-Ret in age-related hearing loss remains uncharacterized.
Purpose of the Study:
- To investigate the role of c-Ret phosphorylation in age-related hearing loss.
- To determine if partial impairment of c-Ret Y1062 phosphorylation affects hearing.
- To explore the underlying mechanisms of c-Ret-associated hearing dysfunction.
Main Methods:
- Generation of heterozygous c-Ret Y1062F knockin mice (c-Ret-KI(Y1062F/+)) to partially impair Y1062 phosphorylation.
- Assessment of hearing levels and SGN integrity in c-Ret-KI(Y1062F/+) mice.
- Comparison with homozygous c-Ret S697A knockin mice (c-Ret-KI(S697A/S697A)) with complete serine 697 (S697) phosphorylation impairment.
- Rescue experiments using constitutively activated RET.
Main Results:
- Partial impairment of c-Ret Y1062 phosphorylation accelerates age-related hearing loss in c-Ret-KI(Y1062F/+) mice.
- Late-onset SGN neurodegeneration was observed in c-Ret-KI(Y1062F/+) mice.
- Complete impairment of c-Ret S697 phosphorylation did not affect hearing in c-Ret-KI(S697A/S697A) mice.
- Accelerated hearing loss was rescued by introducing constitutively activated RET.
Conclusions:
- c-Ret plays a novel role in age-related hearing loss.
- Partial impairment of c-Ret Y1062 phosphorylation is sufficient to accelerate hearing decline and SGN degeneration.
- These findings suggest a shared pathogenesis for distinct c-Ret-related hearing losses, potentially linked to the Y1062F mutation.
