Selective pituitary resistance to thyroid hormone produced by expression of a mutant thyroid hormone receptor beta gene in the pituitary gland of transgenic mice.
Resistance to thyroid hormone (RTH) has been subdivided into generalized resistance (GRTH) and pituitary resistance (PRTH) based on the clinical impression of absence or presence of thyrotoxicosis. However, due to lack of objective clinical and genetic criteria, the existence of PRTH as a distinct entity became controversial. To determine what the phenotype would be if RTH was confined to the pituitary, a transgenic mouse was developed in which expression of the mutant thyroid hormone receptor (TR) beta (G345R) was targeted to the pituitary thyrotrophs by placing it downstream of the mouse thyrotropin beta promoter. This construct exhibited an antagonistic effect on the thyroid hormone-dependent transactivation, mediated through the wild-type TRbeta1, only when cotransfected with the thyrotroph embryonic factor in a heterologous cell line. As expected the transgene was transcribed predominantly in the pituitary gland but not in liver. These mice showed a significant, though modest, increase in serum T4 concentration. A decrease in the serum cholesterol was observed in keeping with the selective tissue hyposensitivity to thyroid hormone.
Hayashi
Y
Y
Department of Medicine, The University of Chicago, Chicago, Illinois, 60637, USA.
Xie
J
J
Weiss
R E
RE
Pohlenz
J
J
Refetoff
S
S
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002784:Cholesterol / Q000097:blood; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013960:Thyroid Function Tests; D013972:Thyrotropin / Q000097:blood / Q000235:genetics; D013974:Thyroxine / Q000097:blood*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014284:Triiodothyronine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D050976:Basic-Leucine Zipper Transcription Factors; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; C489490:TEF protein, human; C489491:Tef protein, mouse; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D002784:Cholesterol; D013974:Thyroxine