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Hönes, G.S.* ; Geist, D.* ; Wenzek, C.* ; Pfluger, P.T. ; Müller, T.D. ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Dragano, N.R.V. ; Garrett, L. ; Hölter, S.M. ; Rathkolb, B. ; Rozman, J. ; Spielmann, N. ; Treise, I. ; Wolf, E.* ; Wurst, W. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Führer, D.* ; Moeller, L.C.*

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

Endocrinology 165:bqae067 (2024)
Postprint DOI PMC
Open Access Green
Free by publisher: Verlagsversion online verfügbar 07/2025
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Endocrinology
Quellenangaben Band: 165, Heft: 8, Seiten: , Artikelnummer: bqae067 Supplement: ,
Verlag Endocrine Society
Verlagsort Chevy Chase, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Institute of Diabetes and Obesity (IDO)
Institute of Developmental Genetics (IDG)
Förderungen 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)