Vujovic Milica, Dudazy-Gralla Susi, Hård Joanna, Solsjö Peter, Warner Amy, Vennström Björn, Mittag Jens
Karolinska Institutet, Department of Cell and Molecular Biology, 17177 Stockholm, Sweden.
Karolinska Institutet, Department of Cell and Molecular Biology, 17177 Stockholm, Sweden; Universität zu Lübeck, Medizinische Klinik 1/Center of Brain, Behavior and Metabolism, Ratzeburger Allee 160, 23562 Lübeck, Germany.
Mol Cell Endocrinol. 2015 Nov 15;416:19-26. doi: 10.1016/j.mce.2015.08.017. Epub 2015 Aug 28.
Thyroid hormone is a well-known regulator of brain, lung and kidney development and function. However, the molecular mechanisms by which the hormone exerts its function have remained largely enigmatic, and only a limited set of target genes have been identified in these tissues. Using a mouse model with a mutation in thyroid hormone receptor α1 (TRα1), we here demonstrate that the expression of carbonic anhydrase 4 in lung and brain of the adult animal depends on intact TRα1 signaling. In the kidney, carbonic anhydrase 4 mRNA and protein are not affected by the mutant TRα1, but are acutely repressed by thyroid hormone. However, neither lung function--as measured by respiration rate and oxygen saturation--nor urine pH levels were affected by altered carbonic anhydrase 4 levels, suggesting that other carbonic anhydrases are likely to compensate. Taken together, our findings identify a previously unknown marker of TRα1 action in brain and lung, and provide a novel negatively regulated target gene to assess renal thyroid hormone status.
甲状腺激素是大脑、肺和肾脏发育及功能的著名调节因子。然而，该激素发挥其功能的分子机制在很大程度上仍然是个谜，并且在这些组织中仅鉴定出有限的一组靶基因。利用甲状腺激素受体α1（TRα1）发生突变的小鼠模型，我们在此证明成年动物肺和脑中碳酸酐酶4的表达依赖于完整的TRα1信号传导。在肾脏中，碳酸酐酶4的mRNA和蛋白质不受突变型TRα1的影响，但会被甲状腺激素急性抑制。然而，无论是通过呼吸频率和血氧饱和度测量的肺功能，还是尿液pH值水平，均未受到碳酸酐酶4水平改变的影响，这表明其他碳酸酐酶可能起到了补偿作用。综上所述，我们的研究结果确定了大脑和肺中TRα1作用的一个此前未知的标志物，并提供了一个新的负调控靶基因来评估肾脏甲状腺激素状态。
