1. LOXHD1 is indispensable for maintaining TMC1 auditory mechanosensitive channels at the site of force transmission.
- Author
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Wang, Pei, Miller, Katharine K., He, Enqi, Dhawan, Siddhant S., Cunningham, Christopher L., and Grillet, Nicolas
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HAIR cells ,LABORATORY mice ,PROTEINS ,ION channels - 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. The Grillet lab identified an additional component of the auditory mechanotransduction Machinery, the protein LOXHD1, which is indispensable to keep the ion channel subunit TMC1 next to the tip-link, where the force induced-by sound is transmitted. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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