Non-canonical action of thyroid hormone receptors α and β

Thyroid hormones (THs) are crucial to maintain a diverse set of physiological functions like organ development, growth, regulation of body temperature, heart rate and certain metabolic processes. TH effects are mediated via the TH receptors (TRs) α and β. TRs act by binding to TH response elements (TREs) on regulatory sequences of target genes. This nuclear signaling is established as the canonical pathway for TH action. In addition, however, TRs can activate intracellular second messenger signaling pathways. Whether such non-canonical TR signaling is physiologically relevant in vivo is unknown, mainly, because a suitable mouse model to study canonical and non-canonical TR action separately in vivo did not exist. To address this issue, two knock-in mouse models (TRαGS and TRβGS) with a mutation in the TR DNA-binding domain were generated. This mutation abrogates binding to TREs and leads to a complete loss of canonical TH actions. Phenotypical comparison of wild-type, TR-knockout and the mutant TRGS mice revealed the physiological relevance of non-canonical TR signaling. Strikingly, several important physiological TH effects were preserved despite disrupted DNA binding: heart rate, body temperature, blood glucose and triglycerides were all regulated by non-canonical TR signaling. In contrast, TRE-binding defective TRβ leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, demonstrating these effects are TRE-mediated and tissue-specific. These results show that the TRαGS and TRβGS mutant mice are suitable models to study non-canonical TR signaling in vivo. Moreover, the present thesis demonstrates that non-canonical TR signaling exerts important physiological effects, which are clearly separated from canonical actions. Consequently, these data challenge the current paradigm that TH actions are mediated exclusively through regulation of gene transcription at the nuclear level.