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Molecular Endocrinology 15 (12): 2115-2128
Copyright © 2001 by The Endocrine Society

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

Carmen Saltó1, Jenny M. Kindblom, Catarina Johansson, Zhendong Wang, Hjalmar Gullberg, Kristina Nordström, Anethe Mansén, Claes Ohlsson, Peter Thorén, Douglas Forrest and Björn Vennström

Department of Cell and Molecular Biology (B.V., C.S., A.M., H.G., K.N.), Department of Physiology (C.J., P.T.), Karolinska Institute, S-171 77 Stockholm, Sweden; Department of Human Genetics (Z.W., D.F.), Mount Sinai School of Medicine, New York, New York 10029; and Endocrine Division (J.M.K., C.O.), Department of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden

Address all correspondence and requests for reprints to: Dr. Björn Vennström, Department of Cell and Molecular Biology, Box 285, Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail: Bjorn.Vennstrom{at}cmb.ki.se

Thyroid hormone governs a diverse repertoire of physiological functions through receptors encoded in the receptor genes {alpha} and ß, which each generate variant proteins. In mammals, the {alpha} gene generates, in addition to the normal receptor TR{alpha}1, a non-hormone-binding variant TR{alpha}2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TR{alpha}2 expression. Selective ablation of TR{alpha}2 resulted in an inevitable, concomitant overexpression of TR{alpha}1. Both TR{alpha}2 +/- 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, TR{alpha}2-/- and TR{alpha}2+/- mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the overexpression of TR{alpha}1 and the concomitant decrease in TR{alpha}2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied.

The phenotypes suggest that the balance of TR{alpha}1:TR{alpha}2 expressed from the TR{alpha} gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.




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