c-Ret–mediated hearing loss in mice with Hirschsprung disease | Zendy

Nobutaka Ohgami | Zendy; Michiru IdaEto | Zendy; Takashi Shimotake | Zendy; Naomi Sakashita | Zendy; Michihiko Sone | Zendy; Tsutomu Nakashima | Zendy; Keiji Tabuchi | Zendy; Tomofumi Hoshino | Zendy; Atsuyoshi Shimada | Zendy; Toyonori Tsuzuki | Zendy; Masahiko Yamamoto | Zendy; Gen Sobue | Zendy; Mayumi Jijiwa | Zendy; Naoya Asai | Zendy; Akira Hara | Zendy; Masahide Takahashi | Zendy; Masashi Kato | Zendy

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c-Ret–mediated hearing loss in mice with Hirschsprung disease

Author(s) -

Nobutaka Ohgami,

Michiru IdaEto,

Takashi Shimotake,

Naomi Sakashita,

Michihiko Sone,

Tsutomu Nakashima,

Keiji Tabuchi,

Tomofumi Hoshino,

Atsuyoshi Shimada,

Toyonori Tsuzuki,

Masahiko Yamamoto,

Gen Sobue,

Mayumi Jijiwa,

Naoya Asai,

Akira Hara,

Masahide Takahashi,

Masashi Kato

Publication year - 2010

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.1004520107

Subject(s) - spiral ganglion , neurodegeneration , sox10 , medicine , proto oncogene proteins c ret , hearing loss , endocrinology , disease , receptor , biology , gene , genetics , glial cell line derived neurotrophic factor , neurotrophic factors , audiology , neural crest

A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-kappaB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans.

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