Disease relevance of Tshr

• These findings, including recruitment-like behavior and the restoration of response magnitude at high levels but not low, suggest that the cochlear amplifier is the primary locus of an enduring otological defect associated with hypothyroidism in the Tshr mouse [1].
• Graves' disease involves a breakdown in self-tolerance to the TSH receptor (TSHR) [2].
• Immunization with adenovirus encoding the TSH receptor (TSHR) or its A-subunit induces Graves' hyperthyroidism in BALB/c and BALB/c x C57BL/6 offspring but not C57BL/6 mice [3].
• CXB strains were studied before and after A-subunit adenovirus immunization for TSHR antibodies (TBI, inhibition of TSH binding), serum T4, and thyroid histology [3].
• Histological and ultrastructural abnormalities in the gland were similar to those seen in certain cases of human congenital hypothyroidism with TSH receptor insensitivity of the thyroid gland [4].

Psychiatry related information on Tshr

• Abnormal neuroanatomical development in selected brain regions may be the factor underlying the abnormalities in reflexive, locomotor, and adaptive behavior seen in the hyt/hyt mouse and other hypothyroid animals [5].
• Mutant (hyt/hyt) mice exhibited a distinctive pattern of sensory pathology that was characterized by their insensitivity to sound, prolonged response latencies, reduced peak amplitudes, and steep latency-intensity curves relative to the phenotypically normal, euthyroid, +/hyt littermates [1].
• The effects of congenital hypothyroidism using the hyt/hyt mouse on locomotor activity and learned behavior [6].

High impact information on Tshr

• We provide evidence for direct effects of TSH on both components of skeletal remodeling, osteoblastic bone formation, and osteoclastic bone resorption, mediated via the TSH receptor (TSHR) found on osteoblast and osteoclast precursors [7].
• The gene for the TSH receptor (TSH-R) was expressed in intestinal T cells but not in epithelial cells, which suggested a hormone-mediated link between lymphoid and nonhematopoietic components of the intestine [8].
• These findings suggest that the hyt mutant gene results in primary hypothyroidism unresponsive to thyroid-stimulating hormone [9].
• The gene, herein named hypothyroid (hyt), has been mapped on chromosome 12 approximately 30 units from the centromere [9].
• Thus, inactivation of the TSHR by stimulating TSHR autoantibodies (TSHR-Ab's) in Graves disease patients may provide a functional explanation for the poor correlation between thyroid function and serum TSHR-Ab concentrations [10].

Chemical compound and disease context of Tshr

• The otological consequences of hypothyroidism and the outcome of thyroxin (T4) administration during the developmental period preceding the onset of hearing were examined in mice that express a point mutation in the gene encoding the thyrotropin receptor (Tshr), the so-called hyt mouse [1].
• The body weight, the weight of different brain regions, and the plasma thyroxine and triiodothyronine levels of hyt/hyt mice were significantly lower than those of the age-matched hyt/+ controls [11].
• To overcome the handicap of very low TSHR expression in thyroid cells, we generated a TSHR-expressing adenovirus (TSHR-Ad-RGD) with an integrin-binding RGD motif enabling efficient entry into cells lacking the coxsackie-adenovirus receptor [12].
• The hyt/hyt mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T4, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake [13].

Biological context of Tshr

• Development of auditory brainstem responses (ABRs) in Tshr mutant mice derived from euthyroid and hypothyroid dams [14].
• The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein-coupled family of receptors whose main function is to regulate thyroid cell proliferation as well as thyroid hormone synthesis and release [15].
• This lack of difference in immune responses in TSHR-knockout and wild-type mice is unexpected and is contrary to observations in other induced animal models of autoimmunity [2].
• Thus, in fully differentiated 3T3-L1 adipocytes, TSH-induced down-regulation of TSHR mRNA levels is evident within 1 h and is near maximum within 4 h after addition of TSH [16].
• In contrast, the down-regulation of TSHR gene expression observed in FRTL-5 cells is sensitive to cycloheximide [16].

Anatomical context of Tshr

• Moreover, T cells from both strains recognized the same two epitopes from a panel of 29 synthetic peptides encompassing the TSHR ectodomain and extracellular loops [2].
• These findings demonstrate that TSH/cAMP regulates TSHR mRNA levels in adipocytes via a regulatory system distinct from that used in FRTL-5 cells [16].
• Nuclear run-on assays show that the ability of TSH/cAMP to decrease TSHR mRNA levels in 3T3-L1 cells reflects transcriptional regulation [16].
• Western blot analyses demonstrated that the mutant and wild-type receptors were processed through a similar series of precursors and that a mature 95-kilodalton form of the mutant TSH-R was produced, consistent with its insertion into the plasma membrane [17].
• We previously have demonstrated that rat adipose tissue expresses TSH receptor (TSHR) messenger RNAs (mRNAs) at levels approaching those detected in the thyroid [16].

Associations of Tshr with chemical compounds

• We conclude that auditory function is impaired in hypothyroid Tshr animals throughout development and that impairment is profound when individuals are not exposed to maternal thyroid hormone, i.e., a clear thyroxin-dependent critical prenatal period exists in the Tshr mutant mouse [14].
• These results suggest interactions between the extracellular and transmembrane domains of the TSH-R and indicate that this highly conserved proline is required for normal receptor structure and function [17].
• It is also shown that while congenital hypothyroid hyt/hyt male mice, exposed to maternal T3 in the gestational period, exhibit diminished but existent androgen-dependent cortical responses, mice exposed to goitrogens during gestation and postnatally are unable to express the gene even at postnatal day ninety [18].
• Replacement of thyroxin during the first 10 postnatal days in hyt/hyt(h) pups had little to no effect on the development of auditory function, although more animals from this group were responsive at very high stimulation levels [14].
• When T4 was administered to hyt/hyt animals, pinna-raising occurred earlier than in untreated animals [1].

Physical interactions of Tshr

• INTRODUCTION: Mouse monoclonal antibodies (mAbs) with the ability to inhibit thyrotropin (TSH) binding to the TSH receptor (TSHR) are useful tools to study TSH-TSHR interaction [19].

Regulatory relationships of Tshr

• Tshrhyt/hyt mutant mice express a point mutation in the gene encoding the thyrotropin receptor, and affected animals are congenitally hypothyroid and profoundly deaf as a consequence when the condition is untreated [20].

Other interactions of Tshr

• Folding-dependent binding of thyrotropin (TSH) and TSH receptor autoantibodies to the murine TSH receptor ectodomain [21].
• This report further demonstrates that adipose cells do not express thyroid transcription factor-1, which interacts with the TSHR promoter region in FRTL-5 cells, and that 3T3-L1 nuclear extracts exhibit a different binding activity to the cAMP-response element-like element in the TSHR promoter region compared with extracts from FRTL-5 cells [16].
• Splenocyte responses to TSHR protein in culture, measured as interferon-gamma production, were similar in TSHR-knockout and wild-type mice [2].
• Consistent with this hypothesis, the DN CREB transgene inhibited the expression of an array of genes including thyroglobulin, thyroperoxidase, and the TSH receptor in semiquantitative RT-PCR experiments [22].
• Subcellular distribution of carbonic anhydrase and Na+,K(+)-ATPase in the brain of the hyt/hyt hypothyroid mice [11].

Analytical, diagnostic and therapeutic context of Tshr

• TSHR antibodies, measured by ELISA, binding to TSHR-expressing eukaryotic cells, and TSH binding inhibition, developed in approximately 60% of TSHR-knockout mice, not significantly different from 80% in the wild-type mice [2].
• We now show that, in Northern blot analyses, TSH-induced down-regulation of TSHR mRNA levels, which can be duplicated by forskolin and dibutylyl cAMP, i.e. which is cAMP-mediated [16].
• Immunofluorescence studies confirmed expression of the P556L mutant on the cell surface of transfected cells and in thyroid tissue from hyt/hyt mice [17].
• Mice lacking murine MHC and expressing human HLA-DR3 develop thyrotropin receptor (TSHR) antibodies and sometimes hyperthyroidism after vaccination with TSHR-DNA [23].
• Through their lifetime, the hyt/hyt mice had reduced serum thyroxine (T4), triiodothyronine (T3), reduced thyroid gland intralumenal colloid on electron microscopy and a 100-fold elevation of TSH-like activity compared to hyt/+ littermates [4].

References