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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 TR 1 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
(Thrbtm1/tm1) mice have a defective
auditory-evoked brainstem response and retarded expression of a
potassium current (IK,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 Thrbtm1/tm1 mice, the deletion
of all TRs in
Thratm1/tm1Thrbtm1/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
IK,f in inner hair cells was not markedly
more retarded than in Thrbtm1/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
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249792-09$05.00/0
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