RT Journal Article
SR Electronic
T1 Myosin-driven Nucleation of Actin Filaments Drives Stereocilia Development Critical for Hearing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.09.451618
DO 10.1101/2021.07.09.451618
A1 Zane G. Moreland
A1 Fangfang Jiang
A1 Carlos Aguilar
A1 Melanie Barzik
A1 Rui Gong
A1 Arik Shams
A1 Christian Faaborg-Andersen
A1 Jesse C. Werth
A1 Randall Harley
A1 Daniel C. Sutton
A1 Stacey M. Cole
A1 Andrew Parker
A1 Susan Morse
A1 Elizabeth Wilson
A1 Yasuharu Takagi
A1 James R. Sellers
A1 Steve D.M. Brown
A1 Thomas B. Friedman
A1 Gregory M. Alushin
A1 Michael R. Bowl
A1 Jonathan E. Bird
YR 2021
UL http://biorxiv.org/content/early/2021/07/13/2021.07.09.451618.abstract
AB The assembly and maintenance of actin-based mechanosensitive stereocilia in the cochlea is critical for lifelong hearing. Myosin-15 (MYO15) is hypothesized to modulate stereocilia height by trafficking actin regulatory proteins to their tip compartments, where actin polymerization must be precisely controlled during development. We identified a mutation (p.D1647G) in the MYO15 motor-domain that initially maintained trafficking, but caused progressive hearing loss by stunting stereocilia growth, revealing an additional function for MYO15. Consistent with its maintenance of tip trafficking in vivo, purified p.D1647G MYO15 modestly reduced actin-stimulated ATPase activity in vitro. Using ensemble and single-filament fluorescence in vitro assays, we demonstrated that wild-type MYO15 directly accelerated actin filament polymerization by driving nucleation, whilst p.D1647G MYO15 blocked this activity. Collectively, our studies suggest direct actin nucleation by MYO15 at the stereocilia tip is necessary for elongation in vivo, and that this is a primary mechanism disrupted in DFNB3 hereditary human hearing loss.Competing Interest StatementThe authors have declared no competing interest.