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

Abstract

Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1, and beta2, bind thyroid hormone (TH) and are considered to be true TRs. TRalpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRalpha (TRalpha(o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T(4)), 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 TRalpha(o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)). In liver, T3 produced significantly greater responses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRalpha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T(4) in TRalpha(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 TRalpha2 in tissues expressing the TRbeta isoforms.

Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice

“…In addition, Tr-β3 and Tr-β3 are not expressed in these mice (Williams, 2000). Thra knockout (Thra 0/0 ) mice have been described previously (Macchia et al, 2001), and lack Thra1 and Thra2 mRNA, as well as Thr a1 and Thr a2 mRNA, which is initiated from an internal promoter in intron 7 that is disrupted in these mice. However, the gene for Rev-erbA-α, which is encoded on the opposite strand to Thra, is still intact.…”

“…Mice were weaned four weeks after birth and were fed mouse chow that contained 0.53 p.p.m. iodine, as described previously in Macchia et al (2001). All animal experiments were performed at the University of Chicago in accordance with protocols approved by the Institutional Animal Care and Use Committee.…”

“…This was due to the targeting of different loci for homologous recombination, which resulted in the loss of different combinations of Tr-α isoforms. Thra knockout mice that lack all Tr-α isoforms (Thra 0/0 ), including short Tr-α isoforms that are generated by internal transcription initiation, are viable and fertile, and have a mild phenotype (Gauthier et al, 2001;Macchia et al, 2001). …”

Interleukin-1β modulates endogenous thyroid hormone receptor α gene transcription in liver cells

“…, upregulation of TRa1 could be an alternative explanation (Macchia et al 2001, Salto et al 2001. Nevertheless, changed tissue responsiveness to T 3 due to a difference in TRa1 and TRa2 expression might be an important regulating mechanism during NTI.…”

Impaired Oxidative Endoplasmic Reticulum Stress Response Caused by Deficiency of Thyroid Hormone Receptor α

“…TR␣-deficient mice (TR␣ 0/0), which lack all known products of the TR␣ gene, were created in the laboratory of Dr. Samarut, as described elsewhere (14). The mice were maintained at the University of Chicago for several generations and back-crossed more than 10 times onto the C57BL/6 background before TR␣ 0/0 male and female mice were given to Dr. Suzuki's laboratory (Fukushima Medical University, F, Japan) and were then kindly given to the present authors by Dr. Suzuki with the permission of Dr. Samarut.…”