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Comparative phenotyping of mice reveals canonical and noncanonical physiological functions of TRα and TRβ.
Endocrinology 165:bqae067 (2024)
DOI
PMC
Thyroid hormone (TH) effects are mediated through TH receptors (TRs) TRα1, TRβ1, and TRβ2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. Aim of this study was to attribute physiological effects to the TR isoforms 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 mutations in the TR DNA-binding domain (TRαGS, TRβGS) and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRβ with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRβ) and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little 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 TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRβ knockout models alongside their DNA-binding-deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRβ play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Mouse Models ; Multi-parameter Phenotyping ; Noncanonical Thyroid Hormone Signaling ; Physiological Thyroid Hormone Effects ; Thyroid Hormome Receptor Alpha ; Thyroid Hormome Receptor Beta; Thyroid-hormone Receptor; Retinal Development; Glucose-transport; Leptin Levels; Dna-binding; Metabolism; Resistance; Lacking; Expression; Thyroxine
ISSN (print) / ISBN
0013-7227
e-ISSN
1945-7170
Journal
Endocrinology
Quellenangaben
Volume: 165,
Issue: 8,
Article Number: bqae067
Publisher
Endocrine Society
Publishing Place
Chevy Chase, Md.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Experimental Genetics (IEG)
Institute of Diabetes and Obesity (IDO)
Institute of Developmental Genetics (IDG)
Institute of Diabetes and Obesity (IDO)
Institute of Developmental Genetics (IDG)
Grants
German Center for Diabetes Research (DZD)
German Federal Ministry of Education and Research
Faculty of Medicine, University of Duisburg-Essen
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
German Federal Ministry of Education and Research
Faculty of Medicine, University of Duisburg-Essen
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)