Different functions for the thyroid hormone receptors TR alpha and TR betain 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 TR alpha and TR beta loci. The existence of sev eral receptor isoforms suggests that different functions are mediated by sp ecific isoforms and raises the possibility of functional redundancies. We h ave inactivated both TR alpha and TR beta genes by homologous recombination in the mouse and compared the phenotypes of wild-type, and single and doub le mutant mice, We show by this method that the TR beta receptors are the m ost potent regulators of the production of thyroid stimulating hormone (TSH ), However, in the absence of TR beta, the products of the TR alpha gene ca n fulfill this function as, in the absence of any receptors, TSH and thyroi d hormone concentrations reach very high levels. We also show that TR beta, in contrast to TR alpha, is dispensable for the normal development of bone and intestine. In bone, the disruption of both TR alpha and TR beta genes does not modify the maturation delay observed in TR alpha(-/-) mice, Tn the ileum, the absence of any receptor results in a much more severe impairmen t than that observed in TR alpha(-/-) 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 fun ctions.