Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing
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 dev...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55898-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585557403762688 |
|---|---|
| author | 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 Jonathan E. Bird |
| author_facet | 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 Jonathan E. Bird |
| author_sort | Zane G. Moreland |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3ae205c4274e45b0888786e03635d1e2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3ae205c4274e45b0888786e03635d1e22025-01-26T12:40:54ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-55898-8Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearingZane G. Moreland0Fangfang Jiang1Carlos Aguilar2Melanie Barzik3Rui Gong4Ghazaleh Behnammanesh5Jinho Park6Arik Shams7Christian Faaborg-Andersen8Jesse C. Werth9Randall Harley10Daniel C. Sutton11James B. Heidings12Stacey M. Cole13Andrew Parker14Susan Morse15Elizabeth Wilson16Yasuharu Takagi17James R. Sellers18Steve D. M. Brown19Thomas B. Friedman20Gregory M. Alushin21Michael R. Bowl22Jonathan E. Bird23Department of Pharmacology and Therapeutics, University of FloridaDepartment of Pharmacology and Therapeutics, University of FloridaMammalian Genetics Unit, MRC Harwell InstituteLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Structural Biophysics and Mechanobiology, The Rockefeller UniversityDepartment of Pharmacology and Therapeutics, University of FloridaDepartment of Pharmacology and Therapeutics, University of FloridaLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthDepartment of Pharmacology and Therapeutics, University of FloridaLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthMammalian Genetics Unit, MRC Harwell InstituteMammalian Genetics Unit, MRC Harwell InstituteLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Molecular Physiology, Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of HealthLaboratory of Molecular Physiology, Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of HealthMammalian Genetics Unit, MRC Harwell InstituteLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of HealthLaboratory of Structural Biophysics and Mechanobiology, The Rockefeller UniversityMammalian Genetics Unit, MRC Harwell InstituteDepartment of Pharmacology and Therapeutics, University of FloridaAbstract 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.https://doi.org/10.1038/s41467-025-55898-8 |
| spellingShingle | 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 Jonathan E. Bird Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing Nature Communications |
| title | Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing |
| title_full | Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing |
| title_fullStr | Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing |
| title_full_unstemmed | Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing |
| title_short | Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing |
| title_sort | myosin based nucleation of actin filaments contributes to stereocilia development critical for hearing |
| url | https://doi.org/10.1038/s41467-025-55898-8 |
| work_keys_str_mv | AT zanegmoreland myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT fangfangjiang myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT carlosaguilar myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT melaniebarzik myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT ruigong myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT ghazalehbehnammanesh myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT jinhopark myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT arikshams myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT christianfaaborgandersen myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT jessecwerth myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT randallharley myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT danielcsutton myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT jamesbheidings myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT staceymcole myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT andrewparker myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT susanmorse myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT elizabethwilson myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT yasuharutakagi myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT jamesrsellers myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT stevedmbrown myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT thomasbfriedman myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT gregorymalushin myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT michaelrbowl myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing AT jonathanebird myosinbasednucleationofactinfilamentscontributestostereociliadevelopmentcriticalforhearing |