Mice devoid of all known thyroid are viable hormone receptors but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation

Thyroid hormone (T3) has widespread functions in development and homeostasis, although the receptor pathways by which this diversity arises are unclear. Deletion of the T3 receptors TRα1 or TRβ individually reveals only a small proportion of the phenotypes that arise in hypothyroidism, implying that additional pathways must exist. Here, we demonstrate that mice lacking both TRα1 and TRβ (TRα1(-/-)β(-/-)) display a novel array of phenotypes not found in single receptor-deficient mice, including an extremely hyperactive pituitary-thyroid axis, poor female fertility and retarded growth and bone maturation. These results establish that major T3 actions are mediated by common pathways in which TRα1 and TRβ cooperate with or substitute for each other. Thus, varying the balance of use of TRα1 and TRβ individually or in combination facilitates control of an extended spectrum of T3 actions. There was no evidence for any previously unidentified T3 receptors in TRα1(-/-)β(-/-) mouse tissues. Compared to the debilitating symptoms of severe hypothyroidism, the milder overall phenotype of TRα1(-/- )β(-/-) mice, lacking all known T3 receptors, indicates divergent consequences for hormone versus receptor deficiency. These distinctions suggest that T3-independent actions of T3 receptors, demonstrated previously in vitro, may be a significant function in vivo.