Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice.
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.
Marians
R C
RC
Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. russell.marians@mssm.edu
Ng
L
L
Blair
H C
HC
Unger
P
P
Graves
P N
PN
Davies
T F
TF
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D018390:Gene Targeting; D005804:Genes, Lethal; D017930:Genes, Reporter; D020249:Hormone Replacement Therapy; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D017136:Ion Transport; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011989:Receptors, Thyrotropin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000187:drug effects; D012974:Sodium Iodide / Q000493:pharmacokinetics; D027981:Symporters / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D013954:Thyroglobulin / Q000096:biosynthesis; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000008:administration & dosage / Q000096:biosynthesis*; D013972:Thyrotropin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D014020:Tissue Extracts / Q000627:therapeutic use; D000099209:Sodium-Iodide Symporters
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D005576:Colforsin; D000242:Cyclic AMP; D004791:Enzyme Inhibitors; D011989:Receptors, Thyrotropin; D012974:Sodium Iodide; D027981:Symporters; D013954:Thyroglobulin; D013963:Thyroid Hormones; D013972:Thyrotropin; D014020:Tissue Extracts; D000099209:Sodium-Iodide Symporters