Human Molecular Genetics Advance Access originally published online on May 5, 2009
Human Molecular Genetics 2009 18(15):2779-2790; doi:10.1093/hmg/ddp213
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Otoferlin interacts with myosin VI: implications for maintenance of the basolateral synaptic structure of the inner hair cell
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1 University of Tübingen, Institute of Human Genetics, Wilhelmstr. 27, 72074 Tübingen, Germany 2 Department of Otorhinolaryngology, University of Tübingen, Tübingen Hearing Research Center (THRC), Molecular Neurobiology and Cell Biology of the Inner Ear, Elfriede-Aulhorn-Str. 5, 72076 Tübingen, Germany 3 University of Tübingen, Institute of Physiology II and Tübingen Hearing Research Centre (THRC), Gmelinstr. 5, 72076 Tübingen, Germany 4 Department of Pharmacology and Toxicology, University of Tübingen, Institute of Pharmacy, Auf der Morgenstelle 8, 72076 Tübingen, Germany 5 Department of Otorhinolaryngology and Institute of Anatomy, University of Tübingen, Elfriede-Aulhorn-Str. 8, 72076 Tübingen, Germany 6 Department of Otorhinolaryngology, University of Tübingen, THRC, Molecular Genetics, Elfriede-Aulhorn-Str. 5, 72076 Tübingen, Germany 7 Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK
* To whom correspondence should be addressed at: HNO-Klinik, Hörforschungszentrum, Elfriede-Aulhorn-Str. 5, 72076 Tübingen, Germany. Tel: +49 70712988244; Fax: +49 7071294950; Email: marlies.knipper{at}uni-tuebingen.de
Received February 18, 2009; Accepted April 30, 2009
Otoferlin has been proposed to be the Ca2+ sensor in hair cell exocytosis, compensating for the classical synaptic fusion proteins synaptotagmin-1 and synaptotagmin-2. In the present study, yeast two-hybrid assays reveal myosin VI as a novel otoferlin binding partner. Co-immunoprecipitation assay and co-expression suggest an interaction of both proteins within the basolateral part of inner hair cells (IHCs). Comparison of otoferlin mutants and myosin VI mutant mice indicates non-complementary and complementary roles of myosin VI and otoferlin for synaptic maturation: (i) IHCs from otoferlin mutant mice exhibited a decoupling of CtBP2/RIBEYE and CaV1.3 and severe reduction of exocytosis. (ii) Myosin VI mutant IHCs failed to transport BK channels to the membrane of the apical cell regions, and the exocytotic Ca2+ efficiency did not mature. (iii) Otoferlin and myosin VI mutant IHCs showed a reduced basolateral synaptic surface area and altered active zone topography. Membrane infoldings in otoferlin mutant IHCs indicated disturbed transport of endocytotic membranes and link the above morphological changes to a complementary role of otoferlin and myosin VI in transport of intracellular compartments to the basolateral IHC membrane.
These authors contributed equally to this work.
Present address: Department of Biomedical Science, University of Sheffield, Sheffield, S10 2TN, UK.
¶ Present address: Department of Biophysics, Saarland University, 66421 Homburg/Saar, Germany.
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  I. Roux, S. Hosie, S. L. Johnson, A. Bahloul, N. Cayet, S. Nouaille, C. J. Kros, C. Petit, and S. Safieddine Myosin VI is required for the proper maturation and function of inner hair cell ribbon synapses Hum. Mol. Genet., December 1, 2009; 18(23): 4615 - 4628. [Abstract] [Full Text] [PDF]
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