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https://hdl.handle.net/20.500.14094/90007363
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2024-04-23
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90007363 (fulltext)
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90007363
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open access
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タイトル
The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia
著者
Ninoyu, Yuzuru ; Sakaguchi, Hirofumi ; Lin, Chen ; Suzuki, Toshiaki ; Hirano, Shigeru ; Hisa, Yasuo ; Saito, Naoaki ; Ueyama, Takehiko
著者名
Ninoyu, Yuzuru
著者名
Sakaguchi, Hirofumi
著者名
Lin, Chen
著者名
Suzuki, Toshiaki
著者名
Hirano, Shigeru
著者名
Hisa, Yasuo
著者ID
A0754
研究者ID
1000060178499
著者名
Saito, Naoaki
齋藤, 尚亮
サイトウ, ナオアキ
所属機関名
バイオシグナル総合研究センター
著者ID
A1239
研究者ID
1000080346254
KUID
https://kuid-rm-web.ofc.kobe-u.ac.jp/search/detail?systemId=443e05a0c3fc0358520e17560c007669
著者名
Ueyama, Takehiko
上山, 健彦
ウエヤマ, タケヒコ
所属機関名
バイオシグナル総合研究センター
収録物名
Cell Death & Disease
巻(号)
11(7)
ページ
536-536
出版者
Springer Nature
刊行日
2020-07-16
公開日
2020-08-11
抄録
Dia1, which belongs to the diaphanous-related formin family, influences a variety of cellular processes through straight actin elongation activity. Recently, novel DIA1 mutants such as p.R1213X (p.R1204X) and p.A265S, have been reported to cause an autosomal dominant sensorineural hearing loss (DFNA1). Additionally, active DIA1 mutants induce progressive hearing loss in a gain-of-function manner. However, the subcellular localization and pathological function of DIA1(R1213X/R1204X) remains unknown. In the present study, we demonstrated the localization of endogenous Dia1 and the constitutively active DIA1 mutant in the cochlea, using transgenic mice expressing FLAG-tagged DIA1(R1204X) (DIA1-TG). Endogenous Dia1 and the DIA1 mutant were regionally expressed at the organ of Corti and the spiral ganglion from early life; alongside cochlear maturation, they became localized at the apical junctional complexes (AJCs) between hair cells (HCs) and supporting cells (SCs). To investigate HC vulnerability in the DIA1-TG mice, we exposed 4-week-old mice to moderate noise, which induced temporary threshold shifts with cochlear synaptopathy and ultrastructural changes in stereocilia 4 weeks post noise exposure. Furthermore, we established a knock-in (KI) mouse line expressing AcGFP-tagged DIA1(R1213X) (DIA1-KI) and confirmed mutant localization at AJCs and the tips of stereocilia in HCs. In MDCK(AcGFP-DIA1(R1213X))cells with stable expression of AcGFP-DIA1(R1213X), AcGFP-DIA1(R1213X) revealed marked localization at microvilli on the apical surface of cells and decreased localization at cell-cell junctions. The DIA1-TG mice demonstrated hazy and ruffled circumferential actin belts at AJCs and abnormal stereocilia accompanied with HC loss at 5 months of age. In conclusion, Dia1 plays a pivotal role in the development and maintenance of AJCs and stereocilia, ensuring cochlear and HC integrity. Subclinical/latent vulnerability of HCs may be the cause of progressive hearing loss in DFNA1 patients, thus suggesting new therapeutic targets for preventing HC degeneration and progressive hearing loss associated with DFNA1.
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バイオシグナル総合研究センター
学術雑誌論文
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© The Author(s) 2020.
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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資源タイプ
journal article
言語
English (英語)
eISSN
2041-4889
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DOI
https://doi.org/10.1038/s41419-020-02743-z
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