Ablation of TRalpha2 and a concomitant overexpression of alpha1 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 alpha and beta, which each generate variant proteins. In mammals, the alpha gene generates, in addition to the normal receptor TRalpha1, a non-hormone-binding variant TRalpha2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TRalpha2 expression. Selective ablation of TRalpha2 resulted in an inevitable, concomitant overexpression of TRalpha1. Both TRalpha2 +/- 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, TRalpha2-/- and TRalpha2+/- mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the overexpression of TRalpha1 and the concomitant decrease in TRalpha2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied. The phenotypes suggest that the balance of TRalpha1:TRalpha2 expressed from the TRalpha gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.

Keyword

Animals

Blotting

Northern

Body Composition

Bone Density

Crosses

Genetic

DNA-Binding Proteins

biosynthesis

genetics

physiology

Female

Gene Expression Regulation

physiology

Histocytochemistry

Hyperthyroidism

genetics

metabolism

Hypothyroidism

genetics

metabolism

Male

Mice

Mice

Inbred BALB C

Mice

Knockout

Phenotype

RNA

chemistry

isolation & purification

Receptors

Cytoplasmic and Nuclear

biosynthesis

genetics

physiology

Receptors

Thyroid Hormone

Reverse Transcriptase Polymerase Chain Reaction

Telemetry

Thyroxine

blood

Triiodothyronine

blood

Publication and Content Type

ref (subject category)

art (subject category)