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Thyroid hormone action: insight from transgenic mouse models
1Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. fwondisf@medicine.bsd.uchicago.edu
Abstract:
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: a and beta. 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-beta isoforms control central regulation of thyroid-stimulating hormone. Of these isoforms, TR-beta2 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 (delta337T) from the TR-beta 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.
Insights
Thyroid hormone receptors (TRs) mediate hypothyroidism effects, even without binding thyroid hormone. The unliganded TR beta isoform is crucial for hypothyroidism
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).
- 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.
