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

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.