Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor β: Evidence for tissue-specific modulation of receptor function

Douglas Forrest, Elizabeth Hanebuth, Richard J. Smeyne, Nancy Everds, Colin L. Stewart, Jeanne M. Wehner, Tom Curran

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352 Scopus citations

Abstract

The diverse functions of thyroid hormone (T3) are presumed to be mediated by two genes encoding the related receptors, TRα and TRβ. However, the in vivo functions of TRα and TRβ are undefined. Here, we report that targeted inactivation of the mouse TRβ gene results in goitre and elevated levels of thyroid hormone. Also, thyroid-stimulating hormone (TSH), which is released by pituitary thyrotropes and which is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb(-/-)) 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(-/-) mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH) that exhibits a similar endocrine disorder but which is typically caused by dominant TRβ mutants that are transcriptional inhibitors. It is unknown whether TRα, TRβ or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb(-/-) mice suggests that antagonism of TRβ-mediated pathways underlies the disorder of the pituitary-thyroid axis. Interestingly, in the brain, the absence of TRβ may not mimic the defects often associated with dominant RTH, since no overt behavioural or neuroanatomical abnormalities were detected in Thrb(-/-) mice. These data define in vivo functions for TRβ and indicate that specificity in T3 signalling is conferred by distinct receptor genes.

Original languageEnglish
Pages (from-to)3006-3015
Number of pages10
JournalEMBO Journal
Volume15
Issue number12
DOIs
StatePublished - 1996

Keywords

  • Genetic disease
  • Thyroid hormone receptor
  • Transcription
  • c-erbA

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