Article Text

Thyroid Hormone Action: Insight from Transgenic Mouse Models
  1. Fredric E. Wondisford
  1. From the Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, IL.
  1. This article was generated from the author’s talk given at the time of receipt of the AFMR award. He was the recipient of the CR2003 Outstanding Investigator Award.
  2. Address correspondence to: Fredric E. Wondisford, MD, Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, IL 60637. E-mail: fwondisf{at}


Thyroid hormone receptors (TRs) are cellular homologues of the viral erythroblastic leukemia oncogene (v-erbA). TRs (c-crbA isoforms) are derived from two separate gene loci in mammals: α and β. Through a series of knockout experiments in mice in which one or several of the TR isoforms were deleted, it has been demonstrated that the TR-β isoforms control central regulation of thyroid-stimulating hormone. Of these isoforms, TR-β2 is the most important in mediating negative feedback control of the hypothalamic-pituitary-thyroid axis. Further analysis of TR knockout animals revealed, however, that they exhibited a much milder overall phenotype than hypothyroid animals, indicating that receptor loss was not equivalent to ligand loss in vivo. To understand this apparent paradox, we generated animals expressing a non-T3 binding receptor (Δ337T) from the TR-β allele. These mice displayed a complete hypothyroid phenotype, demonstrating that the unliganded TR mediates the effect of hypothyroidism. Because this mutant TR constitutively binds to nuclear coreprssors, it also suggests that this class of proteins is essential for mediating hypothyroidism in vivo.

Key Words
  • thyroid hormone receptor
  • resistance to thyroid hormone

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