A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells.
Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in...
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2008-10-01
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doaj-c93a49e10cf3424f8f87e51adb39ccf62020-11-25T00:53:43ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042008-10-01410e100020710.1371/journal.pgen.1000207A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells.Ronna HertzanoElla ShalitAgnieszka K RzadzinskaAmiel A DrorLin SongUri RonJoshua T TanAlina Starovolsky ShitritHelmut FuchsTama HassonNir Ben-TalH Lee SweeneyMartin Hrabe de AngelisKaren P SteelKaren B AvrahamMyosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or 'gating' in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI-impaired hair cells, and ultimately leading to deafness.http://europepmc.org/articles/PMC2543112?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ronna Hertzano Ella Shalit Agnieszka K Rzadzinska Amiel A Dror Lin Song Uri Ron Joshua T Tan Alina Starovolsky Shitrit Helmut Fuchs Tama Hasson Nir Ben-Tal H Lee Sweeney Martin Hrabe de Angelis Karen P Steel Karen B Avraham |
spellingShingle |
Ronna Hertzano Ella Shalit Agnieszka K Rzadzinska Amiel A Dror Lin Song Uri Ron Joshua T Tan Alina Starovolsky Shitrit Helmut Fuchs Tama Hasson Nir Ben-Tal H Lee Sweeney Martin Hrabe de Angelis Karen P Steel Karen B Avraham A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. PLoS Genetics |
author_facet |
Ronna Hertzano Ella Shalit Agnieszka K Rzadzinska Amiel A Dror Lin Song Uri Ron Joshua T Tan Alina Starovolsky Shitrit Helmut Fuchs Tama Hasson Nir Ben-Tal H Lee Sweeney Martin Hrabe de Angelis Karen P Steel Karen B Avraham |
author_sort |
Ronna Hertzano |
title |
A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. |
title_short |
A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. |
title_full |
A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. |
title_fullStr |
A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. |
title_full_unstemmed |
A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells. |
title_sort |
myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin vi in the stereocilia of mammalian inner ear hair cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2008-10-01 |
description |
Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or 'gating' in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI-impaired hair cells, and ultimately leading to deafness. |
url |
http://europepmc.org/articles/PMC2543112?pdf=render |
work_keys_str_mv |
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