Thyroid hormone drives the expression of mouse carbonic anhydrase Car4 in kidney, lung and brain

• Mice with a mutant TRα1 have permanently reduced Car4 in lung and brain.
• Renal Car4 expression is suppressed by T3, providing a novel marker for kidney T3 status.
• Mice with a mutant TRα1 have normal respiratory rate, oxygen saturation and urine pH levels.

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.