Ablation of TRα2 and a concomitant overexpression of α1 yields a mixed hypo- and hyperthyroid phenotype in mice

Thyroid hormone governs a diverse repertoire of physiological functions through receptors encoded in the receptor genes α and β, which each generate variant proteins. In mammals, the α gene generates, in addition to the normal receptor TRα1, a non-hormone-binding variant TRα2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TRα2 expression. Selective ablation of TRα2 resulted in an inevitable, concomitant overexpression of TRα1. Both TRα2 +/- and -/- mice show a complex phenotype with low levels of free T₃ and free T₄, and have inappropriately normal levels of TSH. The thyroid glands exhibit mild morphological signs of dysfunction and respond poorly to TSH, suggesting that the genetic changes affect the ability of the gland to release thyroid hormones. However, the phenotype of the mutant mice also has features of hyperthyroidism, including decreased body weight, elevated heart rate, and a raised body temperature. Furthermore, TRα2-/- and TRα2+/-mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the overexpression of TRα1 and the concomitant decrease in TRα2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied. The phenotypes suggest that the balance of TRα1:TRα2 expressed from the TRα gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.