An unliganded thyroid hormone receptor causes severe neurological dysfunction
An unliganded thyroid hormone receptor causes severe neurological dysfunction
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DOI：
10.1073/pnas.051454698
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发表时间：
2001-03-27
影响因子：
11.1
通讯作者：
Wondisford, FE
中科院分区：
文献类型：
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作者：
Hashimoto, K;Curty, FH;Wondisford, FE
先天性甲状腺功能减退症和甲状腺激素（T-3）抵抗综合征与严重的中枢神经系统（CNS）功能障碍相关。由于甲状腺激素被认为主要通过与其核受体（TR）结合而起作用，因此无法解释为何TR敲除动物被报道具有正常的CNS结构和功能。为了进一步研究这种差异，通过同源重组将T-3结合突变引入小鼠TR-β基因座。由于这种T-3结合缺陷，突变TR与辅阻遏蛋白组成型相互作用并模拟甲状腺功能减退状态，而不管循环甲状腺激素浓度如何。结果表明，未配体TR在脑内具有特异性的有害作用，提示TR辅阻遏物在甲减发病中的重要性。
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.