Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system
Divergent roles for thyroid hormone receptor β isoforms in the endocrine axis and auditory system
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DOI：
10.1172/jci6397
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发表时间：
1999-08-01
影响因子：
15.9
通讯作者：
Wondisford, F
中科院分区：
文献类型：
--
作者：
Abel, ED;Boers, ME;Wondisford, F
甲状腺激素受体（TRs）调节许多器官系统中的各种生理功能。TR α和TR β同种型是2种不同基因的产物，β 1和β 2同种型是同一基因的剪接变体。尽管TR α 1和TR β 1广泛表达，但TR β 2亚型的表达主要限于垂体、三碘甲状腺原氨酸反应性TRH神经元、发育中的内耳和视网膜。靶向破坏整个TR β基因座（TR β-null）的小鼠由于促甲状腺激素的中枢调节异常而表现出甲状腺激素水平升高，并且还发展为严重的听力损失。为了阐明TR β 2亚型对体内内分泌和听觉系统功能的贡献，我们产生了具有TR β 2亚型靶向破坏的小鼠。TR β 2缺失小鼠保留了TR α和TR β 1同种型的表达。它们对甲状腺激素的中枢抵抗程度与TR β-null小鼠相似，表明TR β 2在调节下丘脑-垂体-甲状腺轴中的重要作用。生长激素基因表达略有减少。相比之下，TR β 2缺失小鼠没有表现出听力损伤的证据，表明TR β 1和TR β 2在听觉功能的调节中发挥不同的作用。
Thyroid hormone receptors (TRs) modulate various physiological functions in many organ systems. The TR alpha and TR beta isoforms are products of 2 distinct genes, and, the beta 1 and beta 2 isoforms are splice variants of the same gene. Whereas TR alpha 1 and TR beta 1 are widely expressed, expression of the TR beta 2 isoform is mainly limited to the pituitary, triiodothyronine-responsive TRH neurons, the developing inner ear, and the retina. Mice with targeted disruption of the entire TR beta locus (TR beta-null) exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss. To clarify the contribution of the TR beta 2 isoform to the function of the endocrine and auditory systems in vivo, we have generated mice with targeted disruption of the TR beta 2 isoform. TR beta 2-null mice have preserved expression of the TR alpha and TR beta 1 isoforms. They develop a similar degree of central resistance to thyroid hormone as TR beta-null mice, indicating the important role of TR beta 2 in the regulation of the hypothalarnic-pituitary-thyroid axis. Growth hormone gene expression is marginally reduced. In contrast, TR beta 2-null mice exhibit no evidence of hearing impairment, indicating that TR beta 1 and TR beta 2 subserve divergent roles in the regulation of auditory function.