Abstract
Thyroid hormones (T3, T4) play critical roles in development, growth, and metabolism. The action of thyroid hormone is mediated by thyroid hormone receptors (TRs), which are ligand-dependent transcription factors. TRs are encoded by two genes TRα and TRβ. There are four major isoforms produced by alternative splicing, TRα1, TRα2, TRβ1, and TRβ2. Resistance to thyroid hormone (RTH) is a syndrome of disorders of thyroid hormone functions caused by mutation of TRβ gene. To investigate the mechanism of RTH, mouse with a targeted mutation of TRβ gene was generated. The mutated TRβ, TRβPV, which was identified in a patient with RTH, lacks T3-binding activity and acts in a dominant negative manner. TRβPV/PV showed severe RTH, extremely high serum TSH levels in spite of highly elevated thyroid hormone. And they spontaneously developed TSH secreting pituitary tumors. We also analyzed mice lacking all functional TRs, TRα1-/-, TRβ-/- mice and found that they had normal pituitary in spite of highly elevated TSH levels as TRβPV/PV. These results indicate that the loss in negative regulation of TSH is not sufficient to induce TSHoma and unliganded mutant TRβ may play a critical role in the tumorigenesis of thyrotroph.
