Abel E D, Boers M E, Pazos-Moura C, Moura E, Kaulbach H, Zakaria M, Lowell B, Radovick S, Liberman M C, Wondisford F
Thyroid Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
J Clin Invest. 1999 Aug;104(3):291-300. doi: 10.1172/JCI6397.
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 hypothalamic-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.
甲状腺激素受体（TRs）调节许多器官系统中的各种生理功能。TRα和TRβ亚型是两个不同基因的产物，而β1和β2亚型是同一基因的剪接变体。TRα1和TRβ1广泛表达，而TRβ2亚型的表达主要局限于垂体、促甲状腺激素释放激素（TRH）的三碘甲状腺原氨酸反应性神经元、发育中的内耳和视网膜。由于促甲状腺激素的中枢调节异常，靶向破坏整个TRβ基因座（TRβ基因敲除）的小鼠甲状腺激素水平升高，并且还会出现严重的听力损失。为了阐明TRβ2亚型在体内对内分泌和听觉系统功能的贡献，我们构建了靶向破坏TRβ2亚型的小鼠。TRβ2基因敲除小鼠保留了TRα和TRβ1亚型的表达。它们对甲状腺激素产生了与TRβ基因敲除小鼠相似程度的中枢抵抗，表明TRβ2在下丘脑-垂体-甲状腺轴调节中起重要作用。生长激素基因表达略有降低。相比之下，TRβ2基因敲除小鼠没有听力障碍的迹象，表明TRβ1和TRβ2在听觉功能调节中发挥不同的作用。
