Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha

Abstract

Only three of the four thyroid hormone receptor (TR) isoforms, ␣1, ␤1, and ␤2, bind thyroid hormone (TH) and are considered to be true TRs. TR␣2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TR␣ (TR␣ o/o ) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T4), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3 ,5-triiodothyronine, L-T3) given to TH-deprived and to intact TR␣ o/o mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TR␤ (TR␤ ؊/؊ ). In liver, T3 produced significantly greater responses in TR␣ o/o and smaller responses in TR␤ ؊/؊ as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TR␣ o/o , whereas they were similar in WT and TR␤ ؊/؊ mice, supporting the notion that TR␣1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T4 in TR␣ o/o than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive ''silencing'' effect of TR␣2 in tissues expressing the TR␤ isoforms.T hyroid hormone (TH) action is mediated through specific nuclear TH receptors (TRs) functioning as ligand-dependent transcription factors that increase or decrease the expression of target genes (1-3). There are two TR genes. The TR␤ locus generates the ␤1 and ␤2 receptors by using two different promoters and alternative splicing. The TR␣ locus encodes TR␣1, a molecule containing 410 aa, and three proteins that do not bind the ligand, triiodothyronine (T 3 ) (4-7) (GenBank accession no. AI322342). TR␣2, which results from an alternative splicing of the TR␣ primary transcript, has 492 aa, the first 370 of which are identical to TR␣1. TR⌬␣1 and TR⌬␣2, molecules of approximately 154 and 237 aa, respectively, are generated from an internal promoter located in intron 7 of the TR␣ locus (6). The function of TR␣2, which has a wide tissue distribution (8), and that of TR⌬␣1 and TR⌬␣2, found mainly in brain, gut, and lung (6), are still unknown. However, all have been shown to inhibit ligand-dependent transactivation of TR␤ and TR␣1, a phenomenon termed the dominant negative effect (6, 9-11, ** ).The relative contribution of the two TR gene products in mediating TH responses is poorly understood because of the paucity of information regarding in vivo function. In vitro DNA binding studies and functional assays in transfected cells have generated conflicting results concerning the specific effect of TR isoforms in gene regulation (12, 13). Interpretation is complicated, however, because data are derived from artificial systems using the overexpression of chimeric gene constructs that may not be faithful models of events occurring in the...

Novel neuroanatomical pathways for thyroid hormone action in the human anterior pituitary

“…In somatotropes, T 3 increases TRa1, while it decreases TRb2 (7, 31). Serum TSH concentrations are not altered in mice lacking all TRa transcripts (32). This is in contrast with TRb knockout mice, which have increased TSH subunit mRNA content in the anterior pituitary.…”

Thyroid hormone action in metabolic regulation

“…The TRα gene encodes three TRα isoforms, TRα1, TRα2, and TRα3, which differ in their carboxyl terminus due to alternative splicing. TRα1 is able to bind to T3 and activate or repress target genes, whereas TRα2 and TRα3 lose T3 binding capacity and antagonize T3 action (Izumo and Mahdavi, 1988;Mitsuhashi et al, 1988;Macchia et al, 2001). The TRβ gene encodes three TRβ isoforms, TRβ1, TRβ2, and TRβ3, which differ in their amino terminus.…”

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…TRα gene deletions, total or only α1, do not produce important alterations in TH or TSH concentrations [35]. Several mutations naturally occurring in the human TRβ gene (PV, R438C and P453H) were targeted in homologous regions of the TRα1 gene of the mouse [66][67][68].…”