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

Author

Listed:
  • Huang Wang

    (Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University)

  • Haibo Du

    (School of Life Sciences, Shandong University
    Air Force Medical Center, PLA)

  • 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
    Medical School of Chinese PLA)

  • 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
    Shandong Normal University)

  • Qing Lu

    (Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University
    Shanghai Jiao Tong University School of Medicine, Shanghai, China. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases
    Shanghai Jiao Tong University)

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.

Suggested Citation

  • 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 & Qing Lu, 2023. "Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37267-5
    DOI: 10.1038/s41467-023-37267-5
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    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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    Cited by:

    1. Mofan Feng & Xiaoxi Wei & Xi Zheng & Liangjie Liu & Lin Lin & Manying Xia & Guang He & Yi Shi & Qing Lu, 2024. "Decoding Missense Variants by Incorporating Phase Separation via Machine Learning," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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