TR has the dual role to silence gene expression in the absence of hormone and activate genes in the presence of the ligand, triiodothyronine (Thormeyer and Baniahmad, 1999).
Thyroid hormones have numerous critical effects on development in vertebrates, most notably, they are necessary for normal development of the brain in the fetus. T3 may also be important for ovarian follicle development, and maturation of the cumulus-oocyte complex. T3 regulates gene expression largely through a family of nuclear thyroid hormone receptors (Zhang et al., 1997) NCBI Summary:
The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
General function
Receptor, Nucleic acid binding, DNA binding, Transcription factor
Comment
Thyroid hormones are thought to modulate gene expression positively or negatively through interactions with chromatin-associated receptors. Recently, the c-erb A proto-oncogene products have been shown to be nuclear thyroid hormone (T3) receptors (TR) by sequence similarity with other steroid receptors and by their ability to bind thyroid hormone. The rat TR alpha gene encodes several messenger RNA (mRNA) species, generated by differential processing of its transcripts. The rTR alpha 1 receptor is a thyroid hormone-dependent transcriptional factor, which upon binding the T3 responsive element of the alpha-mHC gene, activates expression of this gene in vivo. Alternative splicing can produce marked differences in the functional properties of a transcriptional factor (Izumo and Mahdavi, 1998).
See also Zhang et al., 1997
Cellular localization
Nuclear
Comment
T3 preserves ovarian granulosa cells from chemotherapy induced apoptosis. Verga Falzacappa C et al. Infertility is a dramatic and frequent side effect in women who are undergoing chemotherapy. Actual strategies are mainly focused on oocytes cryopreservation, but this is not always a suitable option. Considering the key role that granulosa cells play in follicles life, we study if thyroid hormone T3 protects rat ovarian granulosa cells from chemotherapy-induced apoptosis.To this aim a cell line was established from fresh isolated rat granulosa cells and named rGROV. Cells were exposed to Paclitaxel and T3 and, apoptosis, cell viability and cell cycle distribution were analyzed under different conditions. Firstly, the integrity of the steroidogenic pathway was demonstrated, and the presence of thyroid receptors, transporters and deiodinases was confirmed by QPCR. Cells were then exposed to Paclitaxel (Ptx) alone or contemporary to T3. MTT and Tunel assays revealed that while there was a relevant percentage of dying cells when exposed to Ptx (40-60%), the percentage was sensibly reduced (20-30%) in favour of living cells, if T3 was present. Cell cycle analysis showed that cells exposed to Ptx alone were firstly collected in G2 and then dyed by apoptosis; on the other hand the T3 granted the cells to cycle regularly and survive Ptx insult. In addition Western blot and FCM analyses confirmed that caspases activation, casp3 and Bax were downregulated by T3 and that Bcl 2 and cyclins A, B together with cdk1 were upregulated by T3.In conclusions we demonstrated that thyroid hormone T3 can counteract the lethal effect of taxol on granulosa cells.
Nuclear entry of proteins the size of thyroid hormone receptors appears to be mediated by an interaction of nuclear localization signals (NLSs) within the proteins. NLSs have been identified in the hinge region of both receptors. The unoccupied thyroid hormone receptor is always found in the nucleus (LaCasse et al., 1993).
The subcellular localization of natural and engineered forms of the chicken thyroid hormone receptor (cTR alpha) is dependent on amino acids encoded in the N-terminal region. The full length receptor protein, cTR alpha-p46, was found to localize exclusively to the nucleus, whereas the N-terminally shorter variant, cTR alpha-p40, localizes to both the nucleus and the cytoplasm. (Andersson and Vennstrom, 1997)
Effect of triiodothyronine on developmental competence of bovine oocytes. Costa NN et al. Developmental competence of invitro-matured bovine oocytes is a limiting factor in production of embryos invitro. Several studies have suggested a potential positive effect of thyroid hormones on cultured oocytes and/or their supporting cells. Therefore, the aim of the present study was to ascertain whether medium supplementation with triiodothyronine (T3) improved subsequent developmental competence of invitro-matured bovine oocytes. For this purpose, we first documented (using reverse transcription PCR) that whereas bovine cumulus cells expressed both thyroid hormone receptor (TR)-a and TR, immature bovine oocytes expressed TRa only. Thereafter, to test the effects of TH on developmental competence, abattoir-derived oocytes were matured invitro in a medium containing 0, 25, 50, or 100 nM T3 and subjected to invitro fertilization. Embryo quality was evaluated by assessing cleavage and blastocyst rates, morphological quality, development kinetics, and total cell number on Day 8 of culture. Notably, addition of 50 or 100 nM T3 to the invitro maturation medium increased (P < 0.05) the rate of hatched blastocysts on the eighth day of culture, as compared with other groups (62.4 11.7, 53.1 16.3, and 32.4 5.3, respectively). Next, the relative expression levels of genes related to embryo quality POU-domain transcription factor (POU5F1) and glucose transporter-1 (GLUT 1) were compared between invivo- and invitro-produced blastocysts. On the basis of the previous experiments, IVP embryos originating from oocytes that were matured invitro in the presence or absence of 50 nM T3 were evaluated. The treatment had no effect (P > 0.05) on gene expression. We concluded that supplementation of bovine oocyte invitro maturation medium with T3 may have a beneficial effect on the kinetics of embryo development.
Triiodothyronine has been found to enhance gonadotropin- and insulin-stimulated morphologic luteinization and progesterone production by porcine granulosa cells in culture (Wakim et al., 1987).
Thyroid hormone has been demonstrated to synergize with FSH to exert stimulatory effects on the differentiation of porcine granulosa cells (Maruo et al., 1992).
See also (Zhang et al., 1997)
Triiodothyronine has been found to enhance gonadotropin- and insulin-stimulated morphologic luteinization and progesterone production by porcine granulosa cells in culture (Wakim et al., 1987). Thyroid hormone has been demonstrated to synergize with FSH to exert stimulatory effects on the differentiation of porcine granulosa cells (Maruo et al., 1992) See also (Zhang et al., 1997).
Expression regulated by
insulin
Comment
It is possible that insulin augments the actions of thyroid hormone by stimulating production of the thyroid hormone nuclear receptor (TR). Insulin significantly stimulates the gene expression of the TR alpha receptor, causing a maximal threefold induction above control TR alpha steady state mRNA levels in time and dose-related fashion in the bovine (Hu et al., 1994).
Ovarian localization
Oocyte, Cumulus, Granulosa, Stromal cells
Comment
Expression of multiple thyroid hormone receptor mRNAs in human oocytes, cumulus cells, and granulosa cells. Zhang SS et al. (1997) Thyroid hormones have diverse effects on ovarian function. We examined the expression of thyroid hormone receptor (TR) mRNAs (including TRalpha-1, TRbeta-1, TRbeta-2, and c-erbAalpha-2 isoforms) in three types of cells from human follicles, and determined the concentration of free tri-iodothyronine (T3) present in human follicular fluid. Human failed-fertilized oocytes, granulosa (GC) and cumulus (CC) cells from patients of the in-vitro fertilization (IVF) programme at Alliant Hospital Fertility Center were used to detect TR mRNA expression using reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Human spermatozoa were also analysed to determine whether results obtained with CC would be affected by the presence of spermatozoa. beta-Actin mRNA was amplified in each cell type as a positive control for the RT-PCR. Our results show that human oocytes express TRalpha-1, TRbeta-1, TRbeta-2, and c-erbAalpha-2 mRNAs and that these same isoforms are expressed in both human granulosa cells and cumulus cells. No differences were detected in the apparent amounts of RT-PCR products when comparing GC with CC, suggesting a similar pattern of expression of these RNAs. beta-actin mRNA was detected in spermatozoa, but TRalpha-1 expression was not detectable. The concentrations of free T3 measured in follicular fluid were similar to, or slightly below, those in serum of euthyroid patients. These data demonstrated that several isoforms of TR mRNA are expressed in the human oocyte, and hence thyroid hormone may have direct affects on the oocyte, as well as on GC and CC. In addition thyroid hormone may have indirect effects on the oocytes via the CC.//////////////////
Thyroid hormone receptors are differentially expressed in granulosa and cervical cells of infertile women. López E et al. (2015) Thyroid hormones are known to exert an important role in reproduction. The objective of this study is to evaluate the expression of thyroid hormone receptors (TR) in granulosa (GC) and cervical cells (CC) of infertile euthyroid women. In a cross-sectional study, we investigated 31 consecutive infertile and 18 fertile women undergoing oocyte retrieval procedures. The expression of TRα1, TRα2 and TRβ was evaluated in GCs and uterine CC from infertile and fertile euthyroid women. β2 adrenergic receptor (ADRβ2) mRNA levels and the expression of genes linked to fertility such as gremlin-1 (GREM1), hyaluronan synthase 2 (HAS2), and prostaglandin-endoperoxide synthase 2 (PTGS2) were also evaluated. In GCs, the expression of the thyroid hormone receptor TRα2, which exerts a dominant negative effect, increased with age in all women tested. TRα2 mRNA was increased in infertile vs. fertile women, in parallel to decreased ADRβ2 mRNA. As expected, the expression of genes associated with fertility (i.e. GREM1 and PTGS2) was downregulated in infertile women, in parallel to decreased ADRβ2 mRNA and increased TRα2 mRNA. In uterine CCs, a positive association of ADRβ2 mRNA with TRα1:TRα2 ratio was observed. Importantly, GCs from infertile women whose oocytes did not result in pregnancy had increased expression of TRα2 (p=0.017), and lower ADRβ2 (p=0.008), GREM1 (p=0.003) and PTGS2 (p=0.002) mRNAs than fertile women whose oocytes resulted in pregnancy. Infertile women also showed more TRα2 (p=0.033) mRNA in CCs than fertile women whose oocytes resulted in pregnancy. The expression of different markers of intracellular thyroid function is linked to fertility status.//////////////////
Nitric oxide and thyroid hormone receptor alpha 1 contribute to ovarian follicular development in immature hyper- and hypo-thyroid rats. Zheng K et al. (2015) Thyroid dysfunction can cause ovarian cycle and ovulatory disturbances, however, the molecular link(s) between these two disorders remains largely unknown. In the current study, we examined the roles of nitric oxide synthase (NOS) and thyroid hormone receptor alpha 1 (TRα1) in these disorders using immature hyper-thyroid (hyper-T) and hypo-thyroid (hypo-T) rats. In comparison to controls, hyper-T rats had higher serum concentrations of triiodothyronine (T3) and thyroxine (T4), whereas hypo-T rats had lower serum T3 and T4. Serum estradiol (E2) level was decreased in both hyper-T and hypo-T animals and serum E2 in hyper-T rats were lower than in hypo-T rats. We found that neuronal NOS (nNOS) and TRα1 were present in oocytes, granulosa cells and theca cells of all examined rat groups. Ovarian nitric oxide (NO) content and the constitutive NOS (cNOS) activity in hyper-T rats were significantly decreased compared with control or hypo-T rats. Moreover, the number of large antral follicles was reduced in hyper-T rats, and number of primordial follicles was decreased in hypo-T rats compared with control rats. In conclusion, we observed an association between thyroid hormone and NO signaling pathways during the process of ovarian follicular development in immature rats. In hyperthyroidism, thyroid hormones induced an estrogen deficiency that inhibited the function of nNOS, resulting in the inhibition of NO synthesis and suppressed development of large antral follicles, while in hypothyroidism only development of primordial follicles was inhibited.//////////////////
Thyroid hormones have diverse effects on ovarian function. We examined the expression of thyroid hormone receptor (TR) mRNAs (including TR alpha-1, TR beta-1, TR beta-2, and c-erbA alpha-2 isoforms) in three types of cells from human follicles. Human failed-fertilized oocytes, granulosa (GC) and cumulus (CC) cells were used to detect TR mRNA expression. Human oocytes express TR alpha-1, TR beta-1, TR beta-2, and c-erbA alpha-2 mRNAs and that these same isoforms are expressed in both human granulosa cells and cumulus cells (Zhang et al., 1997).
Thyroid hormone receptor messenger ribonucleic acid in human granulosa and ovarian stromal cells: Granulosa cells from the preovulatory antral follicles examined showed positive staining for both the thyroid hormone receptor alpha and beta probes. Positive staining of ovarian stromal cells also was observed for both probes. Thyroid hormone receptor mRNAs are expressed in both granulosa cells and ovarian stromal cells found in nonstimulated ovaries (Wakim et al., 1994).
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TR alpha 1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS- and QTend-durations. The mice have a body temperature 0.5 degrees C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TR alpha 1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperature (Wikstrom et al., 1998).
Species: human
Mutation name: T329N - Resistance to thyroid hormone (RTH)
type: naturally occurring fertility: embryonic lethal Comment: Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor-beta (TRbeta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH (Sarkissian et al., 1999).