Distinct roles of stereociliary links in the nonlinear sound processing and noise resistance of cochlear outer hair cells

Woongsu Han, Jeong Oh Shin, Ji Hyun Ma, Hyehyun Min, Jinsei Jung, Jinu Lee, Un Kyung Kim, Jae Young Choi, Seok Jun Moon, Dae Won Moon, Jinwoong Bok, Chul Hoon Kim

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6 Citations (Scopus)

Abstract

Outer hair cells (OHCs) play an essential role in hearing by acting as a nonlinear amplifier which helps the cochlea detect sounds with high sensitivity and accuracy. This nonlinear sound processing generates distortion products, which can be measured as distortion-product otoacoustic emissions (DPOAEs). The OHC stereocilia that respond to sound vibrations are connected by three kinds of extracellular links: tip links that connect the taller stereocilia to shorter ones and convey force to the mechanoelectrical transduction channels, tectorial membrane-attachment crowns (TM-ACs) that connect the tallest stereocilia to one another and to the overlying TM, and horizontal top connectors (HTCs) that link adjacent stereocilia. While the tip links have been extensively studied, the roles that the other two types of links play in hearing are much less clear, largely because of a lack of suitable animal models. Here, while analyzing genetic combinations of tubby mice, we encountered models missing both HTCs and TM-ACs or HTCs alone. We found that the tubby mutation causes loss of both HTCs and TM-ACs due to a mislocalization of stereocilin, which results in OHC dysfunction leading to severe hearing loss. Intriguingly, the addition of the modifier allele modifier of tubby hearing 1 in tubby mice selectively rescues the TM-ACs but not the HTCs. Hearing is significantly rescued in these mice with robust DPOAE production, indicating an essential role of the TM-ACs but not the HTCs in normal OHC function. In contrast, the HTCs are required for the resistance of hearing to damage caused by noise stress.

Original languageEnglish
Pages (from-to)11109-11117
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number20
DOIs
Publication statusPublished - 2020 May 19

Bibliographical note

Funding Information:
We thank Dr. Doris K. Wu and Dr. Jung-Bum Shin for critical reading of the manuscript, Ms. Hyeon-Joo Kim for assistance with illustrations, and Yonsei-Carl Zeiss Advanced Imaging Center at Yonsei University College of Medicine for technical assistance. This research was supported by the Brain Research Program through the National Research Foundation of Korea funded by Ministry of Science, Information and Communications Technology (ICT), and Future Planning (MSIT) Grants 2016M3C7A1913844 and 2015M3C7A1028396 (to C.H.K.); National Research Foundation of Korea Grant funded by the Korean Government (MSIT) Grants NRF-2018R1A5A2025079 and NRF-2019R1A2C3002354 (to C.H.K.) and Grants NRF-2014M3A9D5A01073865, NRF-2016R1A5A2008630, and NRF-2017R1A2B3009133 (to J.B.); Daegu Gyeongbuk Institute of Science and Technology R&D Program of the Ministry of Science, ICT, and Future Planning Grant 18-BD-06 (to C.H.K. and D.W.M.).

Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Doris K. Wu and Dr. Jung-Bum Shin for critical reading of the manuscript, Ms. Hyeon-Joo Kim for assistance with illustrations, and Yonsei-Carl Zeiss Advanced Imaging Center at Yonsei University College of Medicine for technical assistance. This research was supported by the Brain Research Program through the National Research Foundation of Korea funded by Ministry of Science, Information and Communications Technology (ICT), and Future Planning (MSIT) Grants 2016M3C7A1913844 and 2015M3C7A1028396 (to C.H.K.); National Research Foundation of Korea Grant funded by the Korean Government (MSIT) Grants NRF-2018R1A5A2025079 and NRF-2019R1A2C3002354 (to C.H.K.) and Grants NRF-2014M3A9D5A01073865, NRF-2016R1A5A2008630, and NRF-2017R1A2B3009133 (to J.B.); Daegu Gyeongbuk Institute of Science and Technology R&D Program of the Ministry of Science, ICT, and Future Planning Grant 18-BD-06 (to C.H.K. and D.W.M.).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

All Science Journal Classification (ASJC) codes

  • General

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