Ablation of TR 2 and a Concomitant Overexpression of 1 Yields a Mixed Hypo- and Hyperthyroid Phenotype in Mice

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Abstract
Thyroid hormone governs a diverse repertoire of physiological functions through receptors en- coded in the receptor genes and , which each generate variant proteins. In mammals, the gene generates, in addition to the normal receptor TR1, a non-hormone-binding variant TR2 whose exact function is unclear. Here, we present the pheno- type associated with the targeted ablation of TR2 expression. Selective ablation of TR2 resulted in an inevitable, concomitant overexpression of TR1. Both TR2 / and / mice show a com- plex 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, TR2/ and TR2/ mice are obese and exhibit skeletal alterations, as- sociated with a late-onset growth retardation. The results thus suggest that the overexpression of TR1 and the concomitant decrease in TR2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied. The phenotypes suggest that the balance of TR1:TR2 expressed from the TR gene provides an additional level of tuning the control of growth and homeostasis in mammalian species. (Molecular Endocrinology 15: 2115-2128, 2001)

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