Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development

Abstract

The biological activities of thyroid hormones are thought to be mediated by receptors generated by the TRα and TRβ loci. The existence of several receptor isoforms suggests that different functions are mediated by specific isoforms and raises the possibility of functional redundancies. We have inactivated both TRα and TRβ genes by homologous recombination in the mouse and compared the phenotypes of wild-type, and single and double mutant mice. We show by this method that the TRβ receptors are the most potent regulators of the production of thyroid stimulating hormone (TSH). However, in the absence of TRβ, the products of the TRα gene can fulfill this function as, in the absence of any receptors, TSH and thyroid hormone concentrations reach very high levels. We also show that TRβ, in contrast to TRα, is dispensable for the normal development of bone and intestine. In bone, the disruption of both TRα and TRβ genes does not modify the maturation delay observed in TRα -/-mice. In the ileum, the absence of any receptor results in a much more severe impairment than that observed in TRα -/-animals. We conclude that each of the two families of proteins mediate specific functions of triiodothyronin (T3), and that redundancy is only partial and concerns a limited number of functions.

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…Deletion of both α and β TRs is compatible with life [36,37]. This contrasts with the complete TH deficiency in the athyreotic Pax8KO mouse that dies prior to weaning, unless rescued by TH.…”

The history of a developmental stage: Metamorphosis in chordates

“…Indeed, it is an ecological shift that is characterized by modifications like neural maturation, intestine remodeling, or chondrogenesis that are reminiscent of similar events during amphibian metamorphosis. These modifications occur in correlation with a peak of TH production (both T 3 and T 4 ) (Hadj-Sahraoui et al, 2000), and were shown to be under the control of TH and TR (Flamant et al, 2002;Gauthier et al, 1999;Plateroti et al, 1999). Consequently, weaning should be viewed as homologous to classical metamorphosis even if the precise role of THs in controlling this event and the regulatory hierarchy controlled by these hormones should be better analyzed.…”

Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice

“…Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice Thrb knockout mice have elevated thyroid-stimulating hormone (Tsh) and Th levels in their serum, thyroid gland hyperplasia, and a hearing defect (Forrest et al, 1996;Gauthier et al, 1999). Thra/Thrb double-knockout mice have also been generated and, surprisingly, survive, showing that the presence of Trs is not essential for viability (Gauthier et al, 1999;Gothe et al, 1999).…”

“…Thra/Thrb double-knockout mice have also been generated and, surprisingly, survive, showing that the presence of Trs is not essential for viability (Gauthier et al, 1999;Gothe et al, 1999). Although these mice show extreme Th resistance, they do not display the severe, lethal phenotype seen in mice that are congenitally deficient for Th (Flamant et al, 2002).…”