Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice.

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.