Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle.
Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being critical for hearing, the functions of these proteins in the inner ear remain elusive. Here we show that harmonin, a PDZ domain-containing protein, and cadherin 23 are both present in the growing stereocilia and that they bind to each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin b along the actin core of the developing stereocilia. We propose that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia.
Boëda
Batiste
B
Unité de Génétique des Déficits Sensoriels, CNRS URA 1968, 25 rue du Dr. Roux, 75724 Paris cedex 15, France.
El-Amraoui
Aziz
A
Bahloul
Amel
A
Goodyear
Richard
R
Daviet
Laurent
L
Blanchard
Stéphane
S
Perfettini
Isabelle
I
Fath
Karl R
KR
Shorte
Spencer
S
Reiners
Jan
J
Houdusse
Anne
A
Legrain
Pierre
P
Wolfrum
Uwe
U
Richardson
Guy
G
Petit
Christine
C
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000378:metabolism; D004398:Dyneins; D015723:Gene Library; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D000081412:Myosin VIIa; D009218:Myosins / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D020798:Two-Hybrid System Techniques
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D002352:Carrier Proteins; C499091:Cdh23 protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; C000631457:Myo7a protein, rat; D000081412:Myosin VIIa; D020033:Protein Isoforms; C118970:USH1C protein, human; C492262:Ush1c protein, mouse; C492261:Ush1c protein, rat; D009218:Myosins; D004398:Dyneins