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The Journal of Neuroscience, December 15, 2001, 21(24):9792-9800

Retardation of Cochlear Maturation and Impaired Hair Cell Function Caused by Deletion of All Known Thyroid Hormone Receptors

Alfons Rüsch¹, Lily Ng², Richard Goodyear³, Dominik Oliver¹, Igor Lisoukov², Björn Vennström⁴, Guy Richardson³, Matthew W. Kelley⁵, and Douglas Forrest²

¹ Physiologisches Institut and Sektion Sensorische Biophysik, Hals-Nasen-Ohren Klinik, Röntgenweg 11, Universität Tübingen, D-72076 Tübingen, Germany, ² Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, ³ School of Biological Sciences, The University of Sussex, Falmer, Brighton, BN19QG, United Kingdom, ⁴ Department of Cell and Molecular Biology, Karolinska Institute, S-17 177, Stockholm, Sweden, and ⁵ National Institute of Deafness and Communication Disorders, National Institutes of Health, Rockville, Maryland 20850

The deafness caused by early onset hypothyroidism indicates that thyroid hormone is essential for the development of hearing. We investigated the underlying roles of the TR1 and TR thyroid hormone receptors in the auditory system using receptor-deficient mice. TR1 and TR, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TR is required for hearing because TR-deficient (Thrb^tm1/tm1) mice have a defective auditory-evoked brainstem response and retarded expression of a potassium current (I_K,f) in the cochlear inner hair cells. Here, we show that although TR1 is individually dispensable, TR1 and TR synergistically control an extended array of functions in postnatal cochlear development. Compared with Thrb^tm1/tm1 mice, the deletion of all TRs in Thra^tm1/tm1Thrb^tm1/tm1 mice produces exacerbated and novel phenotypes, including delayed differentiation of the sensory epithelium, malformation of the tectorial membrane, impairment of electromechanical transduction in outer hair cells, and a low endocochlear potential. The induction of I_K,f in inner hair cells was not markedly more retarded than in Thrb^tm1/tm1 mice, suggesting that this feature of hair cell maturation is primarily TR-dependent. These results indicate that distinct pathways mediated by TR alone or by TR and TR1 together facilitate control over an extended range of functions during the maturation of the cochlea.

Key words: cochlea; development; tectorial membrane; hair cell; thyroid hormone receptor; transcription factor

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21249792-09$05.00/0

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