Hashimoto K, Curty F H, Borges P P, Lee C E, Abel E D, Elmquist J K, Cohen R N, Wondisford F E
Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3998-4003. doi: 10.1073/pnas.051454698. Epub 2001 Mar 6.
Congenital hypothyroidism and the thyroid hormone (T(3)) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a T(3) binding mutation was introduced into the mouse TR-beta locus by homologous recombination. Because of this T(3) binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.
先天性甲状腺功能减退症和甲状腺激素（T3）抵抗综合征与严重的中枢神经系统（CNS）功能障碍有关。由于甲状腺激素被认为主要通过与其核受体（TRs）结合发挥作用，因此据报道TR基因敲除动物具有正常的CNS结构和功能这一现象无法得到解释。为了进一步研究这种差异，通过同源重组将T3结合突变引入小鼠TR-β基因座。由于这种T3结合缺陷，突变型TR持续与共抑制蛋白相互作用并模拟甲状腺功能减退状态，而与循环甲状腺激素浓度无关。研究发现小脑发育和功能存在严重异常，海马基因表达和学习也出现异常。这些发现证明了未结合配体的TR在大脑中的特异性有害作用，并提示与TR结合的共抑制蛋白在甲状腺功能减退症发病机制中的重要性。
