Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors

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Abstract

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 TRα1 and TRβ thyroid hormone receptors in the auditory system using receptor-deficient mice. TRα1 and TRβ, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TRβ is required for hearing because TRβ-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 TRα1 is individually dispensable, TRα1 and TRβ 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 TRβ-dependent. These results indicate that distinct pathways mediated by TRβ alone or by TRβ and TRα1 together facilitate control over an extended range of functions during the maturation of the cochlea.

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Rüsch, A., Ng, L., Goodyear, R., Oliver, D., Lisoukov, I., Vennström, B., … Forrest, D. (2001). Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors. Journal of Neuroscience, 21(24), 9792–9800. https://doi.org/10.1523/jneurosci.21-24-09792.2001

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