Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors alpha and beta genes
| Autor: | RE Weiss, O Chassande, EK Koo, PE Macchia, K Cua, J Samarut, S Refetoff |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Aging Heterozygote Endocrinology Diabetes and Metabolism Thyroid Gland Thyrotropin Mice Transgenic Biology Thyroid Function Tests Thyroid function tests Mice Endocrinology Internal medicine medicine Animals Receptor Triiodothyronine Thyroid hormone receptor Receptors Thyroid Hormone medicine.diagnostic_test Thyroid Homozygote Alternative Splicing Thyroxine medicine.anatomical_structure Thyroid hormone receptor alpha Thyroid function hormones hormone substitutes and hormone antagonists Hormone |
| Zdroj: | The Journal of endocrinology. 172(1) |
| ISSN: | 0022-0795 |
| Popis: | 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 (TRbeta1, TRbeta2 and TRalpha1) interact with TH while another, TRalpha2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TRalpha and TRbeta genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TRalpha and TRbeta in the same mouse (TRalphao/o; TRbeta-/-) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TRalpha alone does not cause resistance to TH, the absence of TRbeta in the presence of TRalpha results in a 205, 169, 544% increase in serum thyroxine (T(4)), triiodothyronine (T(3)) and TSH concentrations respectively. However, in the absence of TRbeta, loss of one TRalpha allele can worsen the resistance to TH with a 243 and 307% increase in T(4) and T(3) respectively. Similarly, while the heterozygous mouse with a single TRbeta allele shows no alteration in thyroid function, the concomitant deletion of TRalpha 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 T(4) values also seen in wild-type mice. These results demonstrate that (1) unliganded TRalpha or TRbeta are not absolutely necessary for the upregulation of TSH; (2) TRbeta but not TRalpha is sufficient for TH-mediated downregulation of TSH; and (3) TRalpha may partially substitute for TRbeta in mediating a partial TH-dependent TSH suppression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|