Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors α and β genes

R. E. Weiss, O. Chassande, E. K. Koo, P. E. Macchia, K. Cua, J. Samarut, S. Refetoff

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

The maintenance of thyroid hormone (TH) homeostasis is dependent on the synthesis and secretion of TH regulated by TSH. This is achieved, in turn, by the negative feedback of TH on TSH secretion and synthesis, which requires the interaction with TH receptors (TRs). Derived by alternative splicing of two gene transcription products, three TRs (TRβ1, TRβ2 and TRα1) interact with TH while another, TRα2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TRα and TRβ genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TRα and TRβ in the same mouse (TRαo/o; TRβ-/-) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TRα alone does not cause resistance to TH, the absence of TRβ in the presence of TRα results in a 205, 169, 544% increase in serum thyroxine (T4), triiodothyronine (T3) and TSH concentrations respectively. However, in the absence of TRβ, loss of one TRα allele can worsen the resistance to TH with a 243 and 307% increase in T4 and T3 respectively. Similarly, while the heterozygous mouse with a single TRβ allele shows no alteration in thyroid function, the concomitant deletion of TRα brings about mild but significant resistance to TH. Furthermore, the severity of the resistance to TH was noted to decrease with age in parallel with the decrease in serum free T4 values also seen in wild-type mice. These results demonstrate that (1) unliganded TRα or TRβ are not absolutely necessary for the upregulation of TSH; (2) TRβ but not TRα is sufficient for TH-mediated downregulation of TSH; and (3) TRα may partially substitute for TRβ in mediating a partial TH-dependent TSH suppression.

Original languageEnglish (US)
Pages (from-to)177-185
Number of pages9
JournalJournal of Endocrinology
Volume172
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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