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 (TRβ(flox/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 T(4) and rT(3) concentrations with no significant change in serum T(3) levels. Their intrathyroidal free T(4) and rT(3) contents were also elevated, whereas the ratio of serum T(4) to thyroid free T(4) 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 T(4) and in the expression of genes encoding thyroid hormone transporters may contribute to the primary overproduction of T(4) 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.

Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor β

“…However, it is worth noting that serum TSH values are mostly in the normal range and sometimes even in the lower part of the normal range in spite of increased serum TH. This phenomenon suggests either an increased TSH biological activity or a higher sensitivity to TSH by the mutated thyrocytes, in which TRα isoform prevails, as suggested by several studies …”

New insights into thyroid hormone action

“…Using a unique conditionally – targeted thrb mouse model, Selma-Ruby et al have demonstrated a role for TRβ directly in thyroid follicular cells. Thyrocyte-specific deletion of TRβ in mice leads to increased circulating levels of T4 and rT3, low TSH concentration and normal free T3 levels (Selmi-Ruby et al, 2014). Clearly, mice that lack all TRs develop follicular cells.…”

Functional Characterization of 5-Oxoproline Transport via SLC16A1/MCT1

“…Data represent mean Ϯ S.E. family to which SLC16A1 belongs, is a monocarboxylate transporter for thyroid hormones (32)(33)(34)(35)(36)(37). We also studied the effects of hormones as SLC16A2 substrates, including T3 and T4, on transport of 5-oxoproline via SLC16A1.…”