Defining Thyrotropin-Dependent and -Independent Steps of Thyroid Hormone Synthesis by Using Thyrotropin Receptor-Null Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-11, Vol.99 (24), p.15776-15781
• Main Authors: Marians, R. C., Ng, L., Blair, H. C., Unger, P., Graves, P. N., Davies, T. F.
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases - physiology; Anatomy & physiology; Animals; Biological Sciences; Cattle; Colforsin - pharmacology; Cyclic AMP - physiology; Diet; Endocrinology; Enzyme Inhibitors - pharmacology; Epithelial cells; Gene Expression Regulation; Gene Targeting; Genes, Lethal; Genes, Reporter; Hormone Replacement Therapy; Hormones; Hypothyroidism - genetics; Hypothyroidism - metabolism; Iodides; Ion Transport; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins; Receptors; Receptors, Thyrotropin - deficiency; Receptors, Thyrotropin - genetics; Receptors, Thyrotropin - physiology; Reverse Transcriptase Polymerase Chain Reaction; Second Messenger Systems - drug effects; Sodium Iodide - pharmacokinetics; Symporters - biosynthesis; Symporters - deficiency; Symporters - genetics; Thyroglobulin - biosynthesis; Thyroid gland; Thyroid Gland - metabolism; Thyroid Gland - pathology; Thyroid hormones; Thyroid Hormones - administration & dosage; Thyroid Hormones - biosynthesis; Thyrotropin - blood; Thyrotropin - pharmacology; Thyrotropin - physiology; Tissue Extracts - therapeutic use; Weaning
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.242322099

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.