Journal
NEUROBIOLOGY OF AGING
Volume 33, Issue 3, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2011.04.002
Keywords
c-Ret; Age-related deafness; Tyrosine kinase; Spiral ganglion neuron; Neurodegeneration
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [19390168, 20406003, 18790738, 20791232, S0801055]
- JSPS
- Tokyo Biochemical Research Foundation
- Japan Science and Technology Agency
- Uehara Memorial Foundation
- Chubu University
- Grants-in-Aid for Scientific Research [19390168, 23650241, 23791891, 23590448, 22117005, 23249020, 21590436, 18790738, 20791232] Funding Source: KAKEN
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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-KIY1062F/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-KIY1062F/+-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-KIS697A/S697A-mice). The hearing loss involved late-onset neurodegeneration of spiral ganglion neurons in c-Ret-(KIY1062F/+)-mice. Morphological abnormalities in inner-and outer-hair cells and the stria vascularis in c-Ret-KIY1062F/+-mice were undetectable. The acceleration of age-related hearing loss in c-Ret-KIY1062F/(+)-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. (C) 2012 Elsevier Inc. All rights reserved.
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