Endocrine Abstracts

The majority of T₃ actions are mediated by nuclear thyroid hormone receptors (TRα and TRβ), which act as hormone-inducible transcription factors. TRs are constitutively localised to the nucleus and, in the absence of hormone, bind to T₃-response elements (TREs) located in the promoter regions of T₃ target genes to mediate transcriptional repression. Entry of T₃ to the nucleus and high affinity binding to TRs results in de-repression of gene transcription and hormone-dependent activation of target gene expression. Several TRα and TRβ isoforms are transcribed from separate THRA and THRB genes. TRα1, TRβ1 and TRβ2 contain DNA and ligand-binding domains and act as fully functional T₃ receptors, whereas TRα2 lacks hormone-binding activity and acts as a weak antagonist in vitro, although its physiological function is unknown. TRα1 and TRβ1 are expressed widely but their relative levels differ during development and in adulthood due to tissue-specific and temporo-spatial regulation. Expression of TRβ2 is restricted to the hypothalamus and pituitary, where it mediates negative feedback regulation of TRH and TSH secretion, and to the cochlea and retina where it regulates timing of the onset of hearing and colour vision. Studies of mice with deletion or mutations of the Thra and Thrb genes have identified tissue-specific functions for TRα and TRβ. Thus, T₃ actions are mediated predominantly by TRα1 in the brain, heart, skeleton and gastro-intestinal tract and by TRβ1 in the hypothalamus, pituitary, liver and lung, whereas T₃ responses in other tissues such as skeletal muscle and adipose tissue are mediated by both TR isoforms. These studies have revealed the physiological complexity of thyroid hormone action, whilst characterisation of patients with resistance to thyroid hormone due to TR mutations has emphasised the translational importance of studies in genetically modified mice.