Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice
Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice
复制标题
DOI：
10.1016/j.neurobiolaging.2011.04.002
复制
发表时间：
2012-03-01
影响因子：
4.2
通讯作者：
Kato, Masashi
中科院分区：
文献类型：
--
作者：
Ohgami, Nobutaka;Ida-Eto, Michiru;Kato, Masashi
c-Ret 已被证明对神经发育和存活至关重要。我们最近发现，c-Ret 中酪氨酸 1062 (Y1062) 磷酸化的完全损伤会导致纯合 c-Ret 敲入小鼠（c-Ret-KIY1062F/Y1062F-小鼠）中螺旋神经节神经元（SGN）神经变性，导致先天性听力损失。然而，没有信息将 c-Ret 与年龄相关性听力损失联系起来。在这里，我们发现，c-Ret 中 Y1062 磷酸化的部分损伤会加速杂合 c-Ret Y1062F 敲入小鼠（c-Ret-KIY1062F/+-小鼠）中与年龄相关的听力损失。相比之下，c-Ret 中丝氨酸 697 (S697) 磷酸化的完全损伤并不影响 10 个月大纯合 c-Ret S697A 敲入小鼠（c-Ret-KIS697A/S697A-小鼠）的听力水平。听力损失涉及 c-Ret-(KIY1062F/+)-小鼠螺旋神经节神经元迟发性神经变性。 c-Ret-KIY1062F/+-小鼠的内毛细胞和外毛细胞以及血管纹的形态学异常未检测到。通过引入组成型激活的 RET 可以挽救 c-Ret-KIY1062F/(+)-小鼠中年龄相关性听力损失的加速。因此，我们的结果表明，c-Ret 是小鼠中一种新型的与年龄相关的听力损失相关分子。我们的结果表明，这些听力损失部分具有共同的发病机制，即由 c-Ret 中的单点突变 (Y1062F) 单基因引起。 (C) 2012 Elsevier Inc. 保留所有权利。
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.