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Related Experiment Videos

Thyroid hormone action: insight from transgenic mouse models.

Fredric E Wondisford1

  • 1Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. fwondisf@medicine.bsd.uchicago.edu

Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research
|August 22, 2003
PubMed
Summary

Thyroid hormone receptors (TRs) mediate hypothyroidism effects, even without binding thyroid hormone. The unliganded TR beta isoform is crucial for hypothyroidism

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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Thyroid hormone receptors (TRs) are cellular homologues of the viral erythroblastic leukemia oncogene (v-erbA).
  • TRs, specifically c-erbA isoforms, originate from two gene loci in mammals: alpha and beta.
  • TR-beta isoforms are critical for the central regulation of thyroid-stimulating hormone and negative feedback control of the hypothalamic-pituitary-thyroid axis, with TR-beta2 being most important.

Purpose of the Study:

  • To investigate the role of ligand binding in TR-mediated hypothyroidism.
  • To understand the apparent paradox of milder phenotypes in TR knockout mice compared to hypothyroid animals.
  • To determine if the unliganded TR can mediate hypothyroidism effects in vivo.

Main Methods:

  • Generation of mice expressing a non-T3 binding TR-beta receptor mutant (delta337T).

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  • Analysis of the phenotype of these mutant mice.
  • Assessment of TR binding to nuclear corepressors.

    • Main Results:

    • Mice expressing the non-T3 binding receptor (delta337T) exhibited a complete hypothyroid phenotype.
    • This demonstrates that the unliganded TR mediates the effects of hypothyroidism.
    • The mutant TR constitutively binds to nuclear corepressors, suggesting their essential role in mediating hypothyroidism.

    Conclusions:

    • The unliganded TR beta isoform is sufficient to mediate the effects of hypothyroidism.
    • Ligand-independent functions of TRs are critical for thyroid hormone action in vivo.
    • Nuclear corepressors play an essential role in mediating hypothyroidism through TRs.