Ablation of TR alpha 2 and a concomitant overexpression of alpha 1 yields a mixed hypo- and hyperthyroid phenotype in mice

Thyroid hormone governs a diverse repertoire of physiological functions thr ough receptors encoded in the receptor genes alpha and beta, which each gen erate variant proteins. In mammals, the a gene generates, in addition to th e normal receptor TR alpha1, a non-hormone-binding variant TR alpha2 whose exact function is unclear. Here, we present the phenotype associated with t he targeted ablation of TR alpha2 expression. Selective ablation of TR alph a2 resulted in an inevitable, concomitant overexpression of TR alpha1. Both TR alpha2 +/- and -/- mice show a complex phenotype with low levels of fre e T-3 and free T-4, and have inappropriately normal levels of TSH. The thyr oid glands exhibit mild morphological signs of dysfunction and respond poor ly to TSH, suggesting that the genetic changes affect the ability of the gl and to release thyroid hormones, However, the phenotype of the mutant mice also has: features of hyperthyroidism, including decreased body weight, ele vated heart rate, and a raised body temperature. Furthermore, TR alpha2-/- and TR alpha2+/mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the ove rexpression of TR alpha1 and the concomitant decrease in TR alpha2 expressi on lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissu e studied. The phenotypes suggest that the balance of TR alpha1:TR alpha2 expressed fr om the TR alpha gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.