Both thyroid hormone receptor (TR)β1 and TRβ2 isoforms contribute to the regulation of hypothalamic thyrotropin-releasing hormone
Both thyroid hormone receptor (TR)β1 and TRβ2 isoforms contribute to the regulation of hypothalamic thyrotropin-releasing hormone
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DOI：
10.1210/en.2003-1209
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发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Becker, N
中科院分区：
文献类型：
--
作者：
Dupré, SM;Guissouma, H;Becker, N
甲状腺激素（TH）是脊椎动物发育和代谢的重要调节因子。控制其产生的中枢机制已经进化，其中β-TH受体（TRbeta）在循环TH水平对下丘脑TRH和垂体TSH产生的负反馈效应中发挥关键调节作用。两种TRbeta-isoforms（TRbeta 1和TRbeta 2）都在下丘脑和垂体中表达。然而，它们各自的作用TH依赖的TRH的转录调控是不确定的。我们通过使用TRbeta优先激动剂GC-1证实了TRbeta与TRalpha亚型在野生型小鼠体内TRH调节中的优先作用。接下来，我们确定了通过体细胞基因转移在TRbeta缺失（TRbeta（-/-））小鼠下丘脑中对TRbeta 1和TRbeta 2亚型的组织特异性拯救的效果。TH依赖性TRH转录抑制在TRbeta（-/-）小鼠中受损，但通过将TRbeta 1或TRbeta 2共转染到下丘脑中而恢复。TRbeta 1，而不是TRbeta 2，显示在配体非依赖性激活的作用。用原位杂交技术检测了不同甲状腺状态下TRbeta（-/-）和TRalpha null（TRalpha（o/o））小鼠下丘脑室旁核内源性TRH的表达。与已发表的关于TRbeta 2（-/-）小鼠的数据相反，我们发现TRbeta（-/-）小鼠中配体非依赖性TRH激活和配体依赖性TRH抑制均严重受损。因此，这项研究提供了功能性的体内数据表明，TRbeta 1和TRbeta 2亚型在调节TRH转录的特定作用。
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 andTRbeta2 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.