Dupré Sandrine M, Guissouma Hajer, Flamant Frédéric, Seugnet Isabelle, Scanlan Thomas S, Baxter John D, Samarut Jacques, Demeneix Barbara A, Becker Nathalie
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.
Endocrinology. 2004 May;145(5):2337-45. doi: 10.1210/en.2003-1209. Epub 2004 Jan 15.
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.
甲状腺激素（TH）是脊椎动物发育和新陈代谢的重要调节因子。其产生的中枢调控机制不断进化，β-甲状腺激素受体（TRβ）在循环甲状腺激素水平对下丘脑促甲状腺激素释放激素（TRH）和垂体促甲状腺激素（TSH）产生的负反馈作用中发挥关键调节作用。TRβ的两种亚型（TRβ1和TRβ2）均在下丘脑和垂体中表达。然而，它们在TRH的甲状腺激素依赖性转录调控中的各自作用尚不清楚。我们通过使用TRβ特异性激动剂GC-1，在野生型小鼠体内证实了TRβ亚型相对于TRα亚型在TRH调控中的优先作用。接下来，我们通过体基因转移在TRβ基因敲除（TRβ（-/-））小鼠的下丘脑组织中特异性拯救TRβ1和TRβ2亚型，以确定其效果。在TRβ（-/-）小鼠中，甲状腺激素依赖性TRH转录抑制受损，但通过将TRβ1或TRβ2共转染到下丘脑得以恢复。TRβ1而非TRβ2在非配体依赖性激活中发挥作用。我们使用原位杂交技术检查了不同甲状腺状态下TRβ（-/-）或TRα基因敲除（TRα（o/o））小鼠下丘脑室旁核中内源性TRH的表达。与已发表的关于TRβ2（-/-）小鼠的数据相反，我们发现TRβ（-/-）小鼠中，非配体依赖性TRH激活和配体依赖性TRH抑制均严重受损。因此，本研究提供了体内功能数据，表明TRβ1和TRβ2亚型在调节TRH转录中均具有特定作用。
