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

The diverse functions of thyroid hormone (T3) are presumed to be mediated by two genes encoding the related receptors, TR alpha and TR beta, However, the in vivo functions of TR alpha and TR beta are undefined, Here, we report that targeted inactivation of the mouse TR beta 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 TR beta that cannot be substituted by TR alpha 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 TR beta mutants that are transcriptional inhibitors, It is unknown whether TR alpha, TR beta or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb(-/-) mice suggests that antagonism of TR beta-mediated pathways underlies the disorder of the pituitary-thyroid axis. Interestingly, in the brain, the absence of TR beta 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 TR beta and indicate that specificity in T3 signalling is conferred by distinct receptor genes.