The Targeted Inactivation of TRβ Gene in Thyroid Follicular Cells Suggests a New Mechanism of Regulation of Thyroid Hormone Production

Abstract

Thyroid epithelial cells, or thyrocytes, express functional thyroid hormone receptors but no precise role has yet been assigned to either TRα or TRβ in the thyroid gland. In this study, we analyzed the impact of inactivating the TRβ gene in the thyroid of mice. First, we generated a mouse line named Thyr-Cre, expressing the Cre recombinase under the control of the thyroglobulin gene promoter, which led to a complete recombination of floxed genes in thyrocytes. Thyr-Cre mice were then crossed with TRβ floxed mice (TRβflox/flox) to obtain a thyrocyte-selective deletion of TRβ. Thyr-TRβ−/− mice were characterized by a decrease in the size and functional activity of the thyroid gland. These alterations were associated with a decrease in plasma TSH concentration. Surprisingly, Thyr-TRβ−/− displayed elevated serum T4 and rT3 concentrations with no significant change in serum T3 levels. Their intrathyroidal free T4 and rT3 contents were also elevated, whereas the ratio of serum T4 to thyroid free T4 was decreased by comparison with wild-type littermates. Also, within the thyroid, deiodinases D1 and D2 were reduced as well as the expression levels of genes encoding monocarboxylate transporters (Mct8 and Mct10). Such a decrease in intrathyroidal deiodination of T4 and in the expression of genes encoding thyroid hormone transporters may contribute to the primary overproduction of T4 observed in Thyr-TRβ−/− mice. In conclusion, these data show that the control of thyroid hormone production involves not only TRβ-dependent mechanisms acting at the level of hypothalamus and pituitary but also TRβ-dependent mechanisms acting at the thyroid level.