Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing

Zane G. Moreland, Fangfang Jiang, Carlos Aguilar, Melanie Barzik, Rui Gong, Ghazaleh Behnammanesh, Jinho Park, Arik Shams, Christian Faaborg-Andersen, Jesse C. Werth, Randall Harley, Daniel C. Sutton, James B. Heidings, Stacey M. Cole, Andrew Parker, Susan Morse, Elizabeth Wilson, Yasuharu Takagi, James R. Sellers, Steve D. M. Brown, Thomas B. Friedman, Gregory M. Alushin, Michael R. Bowl () and Jonathan E. Bird ()
Additional contact information
Zane G. Moreland: University of Florida
Fangfang Jiang: University of Florida
Carlos Aguilar: MRC Harwell Institute
Melanie Barzik: National Institutes of Health
Rui Gong: The Rockefeller University
Ghazaleh Behnammanesh: University of Florida
Jinho Park: University of Florida
Arik Shams: National Institutes of Health
Christian Faaborg-Andersen: National Institutes of Health
Jesse C. Werth: National Institutes of Health
Randall Harley: National Institutes of Health
Daniel C. Sutton: National Institutes of Health
James B. Heidings: University of Florida
Stacey M. Cole: National Institutes of Health
Andrew Parker: MRC Harwell Institute
Susan Morse: MRC Harwell Institute
Elizabeth Wilson: National Institutes of Health
Yasuharu Takagi: National Institutes of Health
James R. Sellers: National Institutes of Health
Steve D. M. Brown: MRC Harwell Institute
Thomas B. Friedman: National Institutes of Health
Gregory M. Alushin: The Rockefeller University
Michael R. Bowl: MRC Harwell Institute
Jonathan E. Bird: University of Florida

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Assembly of actin-based stereocilia is critical for cochlear hair cells to detect sound. To tune their mechanosensivity, stereocilia form bundles composed of graded rows of ascending height, necessitating the precise control of actin polymerization. Myosin 15 (MYO15A) drives hair bundle development by delivering critical proteins to growing stereocilia that regulate actin polymerization via an unknown mechanism. Here, we show that MYO15A is itself an actin nucleation-promoting factor. Moreover, a deafness-causing mutation in the MYO15A actin-binding interface inhibits nucleation activity but still preserves some movement on filaments in vitro and partial trafficking on stereocilia in vivo. Stereocilia fail to elongate correctly in this mutant mouse, providing evidence that MYO15A-driven actin nucleation contributes to hair bundle biogenesis. Our work shows that in addition to generating force and motility, the ATPase domain of MYO15A can directly regulate actin polymerization and that disrupting this activity can promote cytoskeletal disease, such as hearing loss.

Date: 2025
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DOI: 10.1038/s41467-025-55898-8

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