TRα2-An Untuned Second Fiddle or Fine-Tuning Thyroid Hormone Action?

Thyroid hormones (THs) control a wide range of physiological functions essential for metabolism, growth, and differentiation. On a molecular level, TH action is exerted by nuclear receptors (TRs), which function as ligand-dependent transcription factors. Among several TR isoforms, the function of TRα2 remains poorly understood as it is a splice variant of TRα with an altered C-terminus that is unable to bind T3. This review highlights the molecular characteristics of TRα2, proposed mechanisms that regulate alternative splicing and indications pointing towards an antagonistic function of this TR isoform in vitro and in vivo. Moreover, remaining knowledge gaps and major challenges that complicate TRα2 characterization, as well as future strategies to fully uncover its physiological relevance, are discussed.