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The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia
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 (DFNA...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366933/ https://www.ncbi.nlm.nih.gov/pubmed/32678080 http://dx.doi.org/10.1038/s41419-020-02743-z |
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author | Ninoyu, Yuzuru Sakaguchi, Hirofumi Lin, Chen Suzuki, Toshiaki Hirano, Shigeru Hisa, Yasuo Saito, Naoaki Ueyama, Takehiko |
author_facet | Ninoyu, Yuzuru Sakaguchi, Hirofumi Lin, Chen Suzuki, Toshiaki Hirano, Shigeru Hisa, Yasuo Saito, Naoaki Ueyama, Takehiko |
author_sort | Ninoyu, Yuzuru |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7366933 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73669332020-07-21 The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia Ninoyu, Yuzuru Sakaguchi, Hirofumi Lin, Chen Suzuki, Toshiaki Hirano, Shigeru Hisa, Yasuo Saito, Naoaki Ueyama, Takehiko Cell Death Dis Article 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. Nature Publishing Group UK 2020-07-16 /pmc/articles/PMC7366933/ /pubmed/32678080 http://dx.doi.org/10.1038/s41419-020-02743-z Text en © The Author(s) 2020 Open Access 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/. |
spellingShingle | Article Ninoyu, Yuzuru Sakaguchi, Hirofumi Lin, Chen Suzuki, Toshiaki Hirano, Shigeru Hisa, Yasuo Saito, Naoaki Ueyama, Takehiko The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia |
title | The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia |
title_full | The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia |
title_fullStr | The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia |
title_full_unstemmed | The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia |
title_short | The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia |
title_sort | integrity of cochlear hair cells is established and maintained through the localization of dia1 at apical junctional complexes and stereocilia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366933/ https://www.ncbi.nlm.nih.gov/pubmed/32678080 http://dx.doi.org/10.1038/s41419-020-02743-z |
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