Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ

Abstract

AbstractThyroid hormone (TH) effects are mediated through TH receptors (TRs) TRα1, TRβ1, and TRβ2. The TRs bind to thyroid hormone responsive elements on the DNA and regulate expression of TH target genes as ligand dependent transcription factors (canonical signaling). In addition, the TRs α and β mediate activation of signaling pathways, e.g. the PI3K/AKT and MAPK/ERK pathways (noncanonical signaling). Whether such DNA-binding independent TR action contributes to the spectrum of physiological TH effects is largely unknown. The aim of this study was to attribute physiological effects to the two TR isoforms α and β and their canonical and noncanonical signaling. We conducted multi-parameter phenotyping in male and female TR knockout mice (TRαKO, TRβKO), mice with disrupted canonical signaling due to a mutation in the TR DNA-binding domain (TRαGS, TRβGS) and their respective wild-type littermates. Perturbations in senses, especially hearing (mainly TRβ with a lesser impact of TRα), visual acuity and retinal thickness (TRα and TRβ), in muscle metabolism (TRα) and in heart rate (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little to no phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization or increased anxiety related behavior were only observed in TRαKO, but not TRαGSmice. Noncanonical TRα action increased the efficiency of energy utilization and prevented hyperphagia observed in TRαKOmice. In summary, by examining the phenotypes of TRα and TRβ knockout models alongside their DNA-binding-deficient GS mutants and wildtype counterparts, we could establish that the independent noncanonical actions of TRα and TRβ play a crucial role in modulating sensory, behavioral, and metabolic functions. This comparison underscores the significance of the TRs in orchestrating a spectrum of physiological processes beyond their traditional genomic pathways.