Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice

Abstract

The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein-coupled family of receptors whose main function is to regulate thyroid cell proliferation as well as thyroid hormone synthesis and release. In this study, we generated a TSHR knockout (TSHR-KO) mouse by homologous recombination for use as a model to study TSHR function. TSHR-KO mice presented with developmental and growth delays and were profoundly hypothyroid, with no detectable thyroid hormone and elevated TSH. Heterozygotes were apparently unaffected. Knockout mice died within 1 week of weaning unless fed a diet supplemented with thyroid powder. Mature mice were fertile on the thyroid-supplemented diet. Thyroid glands of TSHR-KO mice produced uniodinated thyroglobulin, but the ability to concentrate and organify iodide could be restored to TSHR-KO thyroids when cultured in the presence of the adenylate cyclase agonist forskolin. Consistent with this observation was the lack of detectable sodium-iodide symporter expression in TSHR-KO thyroid glands. Hence, by using the TSHR-KO mouse, we provided in vivo evidence, demonstrating that TSHR expression was required for expression of sodium-iodide symporter but was not required for thyroglobulin expression, suggesting that the thyroid hormone synthetic pathway of the mouse could be dissociated into TSHR-dependent and -independent steps.

Evidence for Transcriptional and Posttranscriptional Alterations of the Sodium/Iodide Symporter Expression in Hypofunctioning Benign and Malignant Thyroid Tumors

“…Thus, the impairment of hNIS gene expression occurring in hypofunctioning thyroid tumors could simply result from a switching off of the pathway controlling the expression of hNIS gene. In vitro studies on thyroid cell models and in vivo studies in rodents indicate that the main regulator of NIS gene expression is TSH and that the hormone primarily acts at the level of transcription, [23][24][25][26][27] but also exerts posttranscriptional regulatory actions. 21 Because patients with a cold nodule, be it an adenoma or a carcinoma, are generally euthyroid with a plasma TSH concentration within the normal range, and as TSH receptor expression is maintained in these tumors, 28 it is reasonable to think that the impairment of hNIS expression occurring in hypofunctioning thyroid tumors could result from alterations of regulatory elements along the TSH-activated pathway.…”

Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice

“…FR-Hras G12V mice conditionally express a latent Hras G12V allele under the regulatory control of its endogenous gene promoter (29). TshR-KO mice harbor a germ-line deletion of the TSH receptor (24,47). The gene encoding Gsα was conditionally deleted by using the Gsα-floxed mouse line Gnas-E1 fl/fl , in which loxP recombination sites surround G s α exon 1 at positions −1601 and +419 relative to the translational start site (48).…”

Endocrinology of the mammalian fetal testis

“…In the human fetus, the second trimester pituitary secretes prolactin (PRL), and the PRL receptor is expressed in the testis, but there is no correlation between PRL and testosterone (Fowler et al 2008(Fowler et al , 2009). There are also no reported abnormalities of masculinization in PRL receptor-null mice or, indeed, in GH receptor-null mice or TSH receptor (TSHR)-null mice, while adult males are partially or wholly fertile in all three cases (Ormandy et al 1997, Zhou et al 1997, Marians et al 2002. In conclusion, therefore, it appears that fetal Leydig cells in the mouse are responsive to LH and ACTH but are not critically dependent on them, or any other pituitary hormone, at any time during gestation -unless there is extensive redundancy between the effects of different pituitary hormones.…”