Genetic analysis of thyroid hormone receptors in development and disease

Douglas Forrest, Golijeh Golarai, John Connor, Tom Curran

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31 Scopus citations

Abstract

Thyroid hormone (T3) fulfills diverse functions in vertebrate development and physiology. These functions are thought to be mediated by two genes encoding the related T3 receptors, TRα and TRβ. The use of homologous recombination in embryonic stem cells to generate defined, single-gene mutations provides a powerful means to investigate the individual functions of TRα and TRβ in mice. We have shown that targeted inactivation of the TRβ gene results in goiter and elevated levels of thyroid hormone. Thyroid stimulating hormone (TSH), which is released by pituitary thyrotropes and is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-1-) mice. These findings suggest a unique role for TRβ that cannot be substituted by TRα in the T3-dependent feedback regulation of TSH transcription. Thrb-1- mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH). Typically, RTH is associated with dominant mutations in TRβ. It is unknown whether TRα, TRβ, or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb-1- mice suggests that antagonism of TRβ-mediated pathways underlies the disorder of the pituitary-thyroid axis. Thrb-1- mice also display defective maturation of auditory function, demonstrating that TRβ is essential for the development of hearing. Interestingly, hearing defects are generally absent in dominant RTH, indicating that in the auditory system, a dominant TRβ mutant cannot mimic the defect caused by loss of TRβ. This suggests the existence of tissue-specific mechanisms that modulate the activity of TRβ. These results define in vivo functions for TRβ and indicate that specificity in T3 signaling is conferred by distinct receptor genes.

Original languageEnglish
Pages (from-to)1-22
Number of pages22
JournalRecent Progress in Hormone Research
Volume51
StatePublished - 1996

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