Both thyroid hormone receptor (TR)beta 1 and TR beta 2 isoforms contribute to the regulation of hypothalamic thyrotropin-releasing hormone.
Thyroid hormones (TH) are essential regulators of vertebrate development and metabolism. Central mechanisms governing their production have evolved, with the beta-TH receptor (TRbeta) playing a key regulatory role in the negative feedback effects of circulating TH levels on production of hypothalamic TRH and hypophyseal TSH. Both TRbeta-isoforms (TRbeta1 and TRbeta2) are expressed in the hypothalamus and pituitary. However, their respective roles in TH-dependent transcriptional regulation of TRH are undefined. We confirmed the preferential role of TRbeta vs. TRalpha isoforms in TRH regulation in wild-type mice in vivo by using the TRbeta preferential agonist GC-1. We next determined the effects of tissue-specific rescue of TRbeta1 and TRbeta2 isoforms by somatic gene transfer in hypothalami of TRbeta null (TRbeta(-/-)) mice. TH-dependent TRH transcriptional repression was impaired in TRbeta(-/-) mice, but was restored by cotransfection of either TRbeta1 or TRbeta2 into the hypothalamus. TRbeta1, but not TRbeta2, displayed a role in ligand-independent activation. In situ hybridization was used to examine endogenous TRH expression in the paraventricular nucleus of the hypothalamus of TRbeta(-/-) or TRalpha null (TRalpha(o/o)) mice under different thyroid states. In contrast to published data on TRbeta2(-/-) mice, we found that both ligand-independent TRH activation and ligand-dependent TRH repression were severely impaired in TRbeta(-/-) mice. This study thus provides functional in vivo data showing that both TRbeta1 and TRbeta2 isoforms have specific roles in regulating TRH transcription.
Dupré
Sandrine M
SM
Muséum National d'Histoire Naturelle, Unité Scientifique du Muséum 501 Département Régulation, Développement et Diversité Moléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 5166, 75231 Paris Cedex 05, France.
Guissouma
Hajer
H
Flamant
Frédéric
F
Seugnet
Isabelle
I
Scanlan
Thomas S
TS
Baxter
John D
JD
Samarut
Jacques
J
Demeneix
Barbara A
BA
Becker
Nathalie
N
D000818:Animals; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000737:chemistry*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D008156:Luciferases