Insight into the physiological actions of thyroid hormone receptors from genetically modified mice

Abstract

Thyroid hormones exert a range of developmental and physiological actions in all vertebrates. Serum concentrations of L-thyroxine (T4) and 3,5,3 -L-triiodothyronine (T3) are maintained by a negative feedback loop involving T3-inhibition of hypothalamic thyrotrophin releasing hormone (TRH) and pituitary thyroid stimulating hormone (TSH) secretion, and by tissue specific and hormone-regulated expression of the three iodothyronine deiodinase enzymes that activate or metabolise thyroid hormones. T3 actions are mediated by two T3-receptors, TRalpha and TRbeta, which act as hormone-inducible transcription factors. The TRalpha (NR1A1) and TRbeta (NR1A2) genes encode mRNAs that are alternatively spliced to generate 9 mRNA isoforms (TRalpha1, alpha2, alpha3, Deltaalpha1, Deltaalpha2, beta1, beta2, beta3 and Deltabeta3), of which four (TRalpha1, alpha2, beta1 and beta2) are known to be expressed at the protein level in vivo. The numerous TR mRNAs are expressed widely in tissue- and developmental stage-specific patterns, although it is important to note that levels of mRNA expression may not correlate with receptor protein concentrations in individual tissues. The TRalpha2, alpha3, Deltaalpha1 and Deltaalpha2 transcripts encode proteins that fail to bind T3 in vitro. These non-binding isoforms, in addition to TRDeltabeta3 which does bind hormone, may act as dominant negative antagonists of the true T3-binding receptors in vitro, but their physiological functions and those of the TRbeta3 isoform have not been determined. In order to obtain a new understanding of the complexities of T3 action in vivo and the role of TRs during development, many mouse models of disrupted or augmented thyroid hormone signalling have been generated. The aim of this review is to provide a picture of the physiological actions of thyroid hormones by considering the phenotypes of these genetically modified mice.

Thyroid hormone action during brain development: More questions than answers

“…Despite the widespread distribution of thyroid hormone receptors in the CNS mice deficient in specific receptor isoforms or even in all thyroid hormone receptors do not replicate the strong phenotype of hypothyroid animals indicating that the lack of the ligand T3 has much stronger detrimental consequences than the lack of its receptors (for reviews on the phenotype of thyroid hormone receptor mutant mice see (Forrest and Vennstrom, 2000;O'Shea and Williams, 2002;Flamant and Samarut, 2003;Bernal, 2007). According to the current model that was put forward to explain these discrepancies the structural defects associated with hypothyroidism are primarily caused by unliganded receptors (particularly TRalpha1) that exert aporeceptor activity and thereby repress a program of differentiation.…”

Clinical implications of altered thyroid status in male testicular function

“…It was originally believed that thyroid hormones, due to their lipophilic nature, enter target cells by passive diffusion. Currently, however, there is growing evidence indicating that T4 and T3 cross the plasma membrane by carrier mediated mechanisms (20,21). Several membrane transporter families have been identified, however only monocarboxylate transporter (MCT) 8, MCT 10 and organic anion-transporting polypeptides (OATPs) demonstrate a high degree of specificity towards thyroid hormone (22).…”

Burning hepatic fat: Therapeutic potential for liver-specific thyromimetics in the treatment of nonalcoholic fatty liver disease # †

“…Four of them (TR␣1, TR␣2, TR␤1, and TR␤2) are known to be expressed at the protein level in vivo. 17 The synthesis of compounds that selectively bind TR␤1 has been carried out in recent years. 16 They have been tested on animals, showing that they are able to increase total body oxygen consumption and to lower weight and serum cholesterol and triglyceride levels in rodents.…”