Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation

Huang Wang, Haibo Du, Rui Ren, Tingting Du, Lin Lin, Zhe Feng, Dange Zhao, Xiaoxi Wei, Xiaoyan Zhai, Hongyang Wang, Tingting Dong, Jin-Peng Sun, Hao Wu, Zhigang Xu () and Qing Lu ()
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Huang Wang: Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University
Haibo Du: School of Life Sciences, Shandong University
Rui Ren: School of Life Sciences, Shandong University
Tingting Du: Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases
Lin Lin: Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University
Zhe Feng: School of Life Sciences, Fudan University
Dange Zhao: Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University
Xiaoxi Wei: Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University
Xiaoyan Zhai: School of Life Sciences, Shandong University
Hongyang Wang: Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLA, 28 Fuxing Road
Tingting Dong: Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases
Jin-Peng Sun: Shandong University
Hao Wu: Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases
Zhigang Xu: School of Life Sciences, Shandong University
Qing Lu: Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Stereocilia are actin-based cell protrusions of inner ear hair cells and are indispensable for mechanotransduction. Ankle links connect the ankle region of developing stereocilia, playing an essential role in stereocilia development. WHRN, PDZD7, ADGRV1 and USH2A have been identified to form the so-called ankle link complex (ALC); however, the detailed mechanism underlying the temporal emergence and degeneration of ankle links remains elusive. Here we show that WHRN and PDZD7 orchestrate ADGRV1 and USH2A to assemble the ALC through liquid-liquid phase separation (LLPS). Disruption of the ALC multivalency for LLPS largely abolishes the distribution of WHRN at the ankle region of stereocilia. Interestingly, high concentration of ADGRV1 inhibits LLPS, providing a potential mechanism for ALC disassembly. Moreover, certain deafness mutations of ALC genes weaken the multivalent interactions of ALC and impair LLPS. In conclusion, our study demonstrates that LLPS mediates ALC formation, providing essential clues for understanding the pathogenesis of deafness.

Date: 2023
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DOI: 10.1038/s41467-023-37267-5

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