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The Journal of Neuroscience, February 25, 2009, 29(8):2581-2587; doi:10.1523/JNEUROSCI.3557-08.2009

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Cellular/Molecular
Deafness in TRβ Mutants Is Caused by Malformation of the Tectorial Membrane

Harald Winter,1,2 * Lukas Rüttiger,1,2 * Marcus Müller,1,3 Stephanie Kuhn,1,4 Niels Brandt,1,4 Ulrike Zimmermann,1,2 Bernhard Hirt,1,3,5 Andreas Bress,1,6 Matthias Sausbier,7 Aude Conscience,8,9 Frederic Flamant,8 Yong Tian,10 Jian Zuo,10 Markus Pfister,1,6 Peter Ruth,7 Hubert Löwenheim,1,3 Jacques Samarut,8 Jutta Engel,1,4 and Marlies Knipper1,2

1Department of Otorhinolaryngology, Tübingen Hearing Research Center, 2Molecular Neurobiology and Cell Biology of the Inner Ear, 3Molecular Otology, 4Institute of Physiology II, 5Institute of Anatomy, 6Hereditary Hearing Loss, and 7Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Tübingen, 72076 Tübingen, Germany, 8Institut de Génomique Fonctionnelle, Ecole Normale Supérieure de Lyon, 69364 Lyon, France, 9Monash Immunology and Stem Cell Laboratories, Monash University, Victoria 3800, Australia, and 10Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Correspondence should be addressed to Dr. Marlies Knipper, Hans-Nasen-Ohren-Klinik, Hörforschungszentrum, Elfriede-Aulhorn-Strasse 5, 72076 Tübingen, Germany. Email: marlies.knipper{at}uni-tuebingen.de

Thyroid hormone receptor β (TRβ) dysfunction leads to deafness in humans and mice. Deafness in TRβ–/– mutant mice has been attributed to TRβ-mediated control of voltage- and Ca2+-activated K+ (BK) channel expression in inner hair cells (IHCs). However, normal hearing in young constitutive BK{alpha}–/– mutants contradicts this hypothesis. Here, we show that mice with hair cell-specific deletion of TRβ after postnatal day 11 (P11) have a delay in BK{alpha} expression but normal hearing, indicating that the origin of hearing loss in TRβ–/– mutant mice manifested before P11. Analyzing the phenotype of IHCs in constitutive TRβ–/– mice, we found normal Ca2+ current amplitudes, exocytosis, and shape of compound action potential waveforms. In contrast, reduced distortion product otoacoustic emissions and cochlear microphonics associated with an abnormal structure of the tectorial membrane and enhanced tectorin levels suggest that disturbed mechanical performance is the primary cause of deafness resulting from TRβ deficiency.

Key words: hearing; TRβ; BK; conditional knock-out mice; tectorin; exocytosis

Received July 28, 2008; revised Oct. 27, 2008; accepted Dec. 16, 2008.

Correspondence should be addressed to Dr. Marlies Knipper, Hans-Nasen-Ohren-Klinik, Hörforschungszentrum, Elfriede-Aulhorn-Strasse 5, 72076 Tübingen, Germany. Email: marlies.knipper{at}uni-tuebingen.de
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