Abstract
Hair cell bundles consist of stereocilia arranged in rows of increasing heights, connected by tip links that transmit sound-induced forces to shorter stereocilia tips. Auditory mechanotransduction channel complexes, composed of proteins TMC1/2, TMIE, CIB2, and LHFPL5, are located at the tips of shorter stereocilia. While most components can interact with the tip link in vitro, their ability to maintain the channel complexes at the tip link in vivo is uncertain. Return, using mouse models, we show that an additional component, LOXHD1, is essential for keeping TMC1-pore forming subunits at the tip link but is dispensable for TMC2. Using SUB-immunogold-SEM, we showed that TMC1 localizes near the tip link but mislocalizes without LOXHD1. LOXHD1 selectively interacts with TMC1, CIB2, LHFPL5, and tip-link protein PCDH15. Our results demonstrate that TMC1-driven mature auditory channels require LOXHD1 to stay connected to the tip link and remain functional, while TMC2-driven developmental channels do not.
| Original language | English |
|---|---|
| Article number | 7865 |
| Journal | Nature Communications |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Bibliographical note
Publisher Copyright:© The Author(s) 2024.
Funding
The work was funded by the National Institute on Deafness, and Other Communication Disorders Grants 1R21DC019457-01 (N.G.), 1R01DC016409-01A1 (N.G.), 1R01DC021835-01 (CLC), R21DC019195, the National Institute on Aging Grant 1R01AG081608-01 (N.G.), the Stanford Maternal and Child Health Research Institute (NG), and the OHNS departmental support (N.G.). Part of this work was performed at the Stanford Nano Shared Facilities (SNSF), supported by the National Science Foundation under award ECCS-2026822. We would like to thank Dr. Hong Zeng and the Stanford Transgenic, Knockout & Tumor Model Center, and Dr. Patrick Atkinson and the Otolaryngology Department Imaging and Audiometry core facilities. We would also like to thank Dr. Ulrich Müller, Dr. Zubair Ahmed, and Dr. Arnaud Giese for providing constructs, Dr. Robert Fettiplace and Dr. Marlyn Beurg for sharing the Tmc1 KO mice, Dr. Anthony Ricci for training E.H. with electrophysiology, and providing feedback on the manuscript along with Dr. Dáibhid Ó Maoiléidigh, and Dr. Bertrand Coste. N.G. thanks Lais Priolli for constant support. Finally, we thank Shari and Kenneth Eberts, the Oberndorf family, and the SICHL contributors for their support. The work was funded by the National Institute on Deafness, and Other Communication Disorders Grants 1R21DC019457-01 (N.G.), 1R01DC016409-01A1 (N.G.), 1R01DC021835-01 (CLC), R21DC019195, the National Institute on Aging Grant 1R01AG081608-01 (N.G.), the Stanford Maternal and Child Health Research Institute (NG), and the OHNS departmental support (N.G.). Part of this work was performed at the Stanford Nano Shared Facilities (SNSF), supported by the National Science Foundation under award ECCS-2026822. We would like to thank Dr. Hong Zeng and the Stanford Transgenic, Knockout & Tumor Model Center, and Dr. Patrick Atkinson and the Otolaryngology Department Imaging and Audiometry core facilities. We would also like to thank Dr. Ulrich Müller, Dr. Zubair Ahmed, and Dr. Arnaud Giese for providing constructs, Dr. Robert Fettiplace and Dr. Marlyn Beurg for sharing the Tmc1 mice, Dr. Anthony Ricci for training E.H. with electrophysiology, and providing feedback on the manuscript along with Dr. Dáibhid Ó Maoiléidigh, and Dr. Bertrand Coste. N.G. thanks Lais Priolli for constant support. Finally, we thank Shari and Kenneth Eberts, the Oberndorf family, and the SICHL contributors for their support.
| Funders | Funder number |
|---|---|
| Stanford Transgenic, Knockout & Tumor Model Center | |
| Stanford Maternal and Child Health Research Institute | |
| National Institute on Aging | 1R01AG081608-01 |
| National Institute on Deafness and Other Communication | 1R01DC021835-01, 1R01DC016409-01A1, R21DC019195, 1R21DC019457-01 |
| National Science Foundation Arctic Social Science Program | ECCS-2026822 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy