| vitamin D receptor | OKDB#: 876 |
| Symbols: | VDR | Species: | human | ||
| Synonyms: | NR1I1, PPP1R163 | Locus: | 12q13.11 in Homo sapiens | HPMR |
|
For retrieval of Nucleotide and Amino Acid sequences please go to:
OMIM
Entrez Gene
Mammalian Reproductive Genetics Endometrium Database Resource Orthologous Genes UCSC Genome Browser GEO Profiles new! Amazonia (transcriptome data) new! R-L INTERACTIONS MGI |
| General Comment |
The vitamin D3 receptors are intracellular polypeptides of 50 to 60 kD that specifically bind 1,25(OH)2D3 and interact
with target-cell nuclei to produce a variety of biologic effects. Baker et al. (1988) described the cloning and
characterization of cDNAs encoding the human vitamin D receptor. Analysis of the deduced amino acid sequence
showed that the VDR protein belongs to the superfamily of trans-acting transcriptional regulatory factors, including the
steroid and thyroid hormone receptors. VDR is more closely related to the thyroid hormone receptors than to the others.//////Role of Vitamin D in Female Reproduction. Shahrokhi SZ et al. (2016) Vitamin D is a fat-soluble vitamin that belongs to the family of steroid hormones. The biological actions of vitamin D are exerted through a soluble protein, the vitamin D receptor (VDR). VDR is a transcription factor located in the nuclei of target cells that mediates the genomic action of the active form of vitamin D (1,25(OH)2D3). This transcription factor is distributed in various tissues, including the reproductive system. The presence of VDR in female reproductive tissue suggests that vitamin D is involved in female reproduction. The present article reviews the impact of vitamin D on anti-Müllerian hormone (AMH), as an ovarian reserve marker, and ovarian steroidogenesis. This article also discusses the impact of vitamin D as a factor that influences infertility and the outcome of in vitro fertilization (IVF), insulin resistance (IR), hyperandrogenism, endometriosis and polycystic ovary syndrome (PCOS).//////////////////
NCBI Summary: This gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. This receptor also functions as a receptor for the secondary bile acid, lithocholic acid. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018] |
||||
| General function | Receptor, Nucleic acid binding, DNA binding, Transcription factor | ||||
| Comment | Lower follicular fluid vitamin D concentration is related to a higher number of large ovarian follicles. Antunes RA et al. (2018) Vitamin D receptor-knockout mice fail to produce mature oocytes, indicating vitamin D is crucial for folliculogenesis in mice. However, the actions of vitamin D during folliculogenesis remain unknown. This prospective study aimed to assess whether follicular fluid (FF) vitamin D (25OHD3) concentrations are related to specific responses to ovarian stimulation. Women undergoing ovarian stimulation for IVF participated in the study. FF 25OHD3 concentrations were assessed in the first follicle aspirate on oocyte retrieval day. Oestradiol and progesterone concentrations were assessed on the trigger day. K-means grouping analysis showed that 25OHD3 FF concentrations clustered into a higher and lower group (mean ± SEM 17.4 ± 6.61 ng/ml and 35.5 ± 7.17 ng/ml, respectively, P < 0.001). The clusters were analysed according to the oestradiol and progesterone concentrations, follicle number and size and resulting oocyte number and maturity. The FF 25OHD3 concentrations were no different among the infertility diagnoses. The lower 25OHD3 group had more follicles (≥16.0 mm, P = 0.009) and higher serum oestradiol concentrations (P < 0.03) on the day of HCG administration. In this study, lower follicular 25OHD3 concentrations predicted a better response to ovarian stimulation shown by a greater production of larger follicles and higher serum oestradiol concentrations.////////////////// | ||||
| Cellular localization | Nuclear | ||||
| Comment | candidate123 | ||||
| Ovarian function | Follicle development, Preantral follicle growth, Antral follicle growth, Ovulation, Steroid metabolism | ||||
| Comment | Vitamin D3 Regulates Follicular Development and Intrafollicular Vitamin D Biosynthesis and Signaling in the Primate Ovary. Xu J et al. (2018) There is an increasing recognition that vitamin D plays important roles in female reproduction. Recent studies demonstrated that 1α,25-dihydroxyvitamin D3 (VD3), the biologically active form of vitamin D, improved ovarian follicle survival and growth in vitro. Therefore, we investigated the direct effects of VD3 at the specific preantral and antral stages of follicular development, and tested the hypothesis that vitamin D receptor (VDR) and enzymes critical for vitamin D biosynthesis are expressed in the primate ovary. Fourteen adult rhesus macaques provided ovarian tissue. Secondary and antral follicles were isolated for PCR analysis on VDR, vitamin D3 25-hydroxylase, and 25-hydroxyvitamin D3-1α-hydroxylase. VDR protein localization was determined by immunohistochemistry on ovarian sections. Isolated secondary follicles were cultured under conditions of control and VD3 supplementation during the preantral or antral stage. Follicle survival, growth, steroid and anti-Müllerian hormone (AMH) production, as well as oocyte maturation were evaluated. In vivo- and in vitro-developed follicles were also assessed for genes that are critical for vitamin D biosynthesis and signaling, gonadotropin signaling, steroid and paracrine factor production, and oocyte quality. The mRNA encoding VDR, 25-hydroxylase, and 1α-hydroxylase was detectable in in vivo- and in vitro-developed preantral and antral follicles. The 25-hydroxylase was elevated in cultured follicles relative to in vivo-developed follicles, which further increased following VD3 exposure. VD3 treatment increased 1α-hydroxylase in in vitro-developed antral follicles. The absence of VD3 during culture decreased VDR expression in in vitro-developed antral follicles, which was restored to levels comparable to those of in vivo-developed antral follicles by VD3 supplementation. Positive immunostaining for VDR was detected in the nucleus and cytoplasm of granulosa cells and oocytes. While only survival was improved in preantral follicles treated with VD3, VD3 supplementation promoted both survival and growth of antral follicles with increased estradiol and AMH production, as well as oocyte maturation. Thus, Vitamin D biosynthesis and signaling systems are expressed in primate ovarian follicles. Our findings support a role for VD3 in regulating follicular development in a stage-dependent manner, as well as the intrafollicular vitamin D biosynthesis and signaling, directly in the ovary.////////////////// Effect of vitamin D3 on production of progesterone in porcine granulosa cells by regulation of steroidogenic enzymes. Hong SH et al. (2016) 1,25-dihydroxyvitamin D3 (VD3), an active form of Vitamin D, is photosynthesized in the skin of vertebrates in response to solar ultraviolet B radiation (UV-B). VD3 deficiency can cause health problems such as immune disease, metabolic disease, and bone disorders. It has also been demonstrated that VD3 is involved in reproductive functions. Female sex hormones such as estrogen and progesterone are biosynthesized mainly in ovarian granulosa cells as the ovarian follicle develops. The functions of sex hormones include regulation of the estrus cycle and puberty as well as maintenance of pregnancy in females. In this study, we isolated granulosa cells from porcine ovaries and cultured them for experiments. To examine the effects of VD3 on ovarian granulosa cells, the mRNA and protein levels of genes were analyzed by Real-time PCR and Western blotting assay. Production of progesterone from granulosa cells was also measured by ELISA assay. As a result, transcriptional and translational regulation of progesterone biosynthesis-related genes in granulosa cells was significantly altered by VD3. Furthermore, progesterone concentrations in porcine granulosa cell-cultured media decreased in response to VD3. These results show that VD3 was a strong regulator of sex steroid hormone production in porcine granulosa cells, suggesting that vitamin D deficiency may result in inappropriate sexual development of industrial animals and eventually economic loss. ////////////////// 1,25-Dihydroxyvitamin D3 increases testosterone-induced 17beta-estradiol secretion and reverses testosterone-reduced connexin 43 in rat granulosa cells. Lee CT 2014 et al. BACKGROUND Aromatase converts testosterone into 17beta-estradiol in granulosa cells, and the converted 17beta-estradiol contributes to follicular maturation. Additionally, excessive testosterone inhibits aromatase activity, which can lead to concerns regarding polycystic ovary syndrome (PCOS). Generally, 1,25-dihydroxyvitamin D3 (1,25D3) supplements help to improve the symptoms of PCOS patients who exhibit low blood levels of 1,25D3. Therefore, this study investigated the interaction effects of 1,25D3 and testosterone on estrogenesis and intercellular connections in rat granulosa cells. METHODS Primary cultures of granulosa cells were treated with testosterone or testosterone plus 1,25D3, or pre-treated with a calcium channel blocker or calcium chelator. Cell lysates were subjected to western blot analysis to determine protein and phosphorylation levels, and 17beta-estradiol secretion was examined using a radioimmunoassay technique. Cell viability was evaluated by MTT reduction assay. Connexin 43 (Cx43) mRNA and protein expression levels were assessed by qRT-PCR, western blot, and immunocytochemistry. RESULTS Testosterone treatment (0.1 and 1 microg/mL) increased aromatase expression and 17beta-estradiol secretion, and the addition of 1,25D3 attenuated testosterone (1 microg/mL)-induced aromatase expression but improved testosterone-induced 17beta-estradiol secretion. Furthermore, testosterone-induced aromatase phosphotyrosine levels increased at 10 min, 30 min and 1 h, whereas 1,25D3 increased the longevity of the testosterone effect to 6 h and 24 h. Within 18-24 h of treatment, 1,25D3 markedly enhanced testosterone-induced 17beta-estradiol secretion. Additionally, pre-treatment with a calcium channel blocker nifedipine or an intracellular calcium chelator BAPTA-AM reduced 1,25D3 and testosterone-induced 17beta-estradiol secretion. Groups that underwent testosterone treatment exhibited significantly increased estradiol receptor beta expression levels, which were not affected by 1,25D3. Neither testosterone nor 1,25D3 altered 1,25D3 receptor expression. Finally, at high doses of testosterone, Cx43 protein expression was decreased in granulosa cells, and this effect was reversed by co-treatment with 1,25D3. CONCLUSIONS These data suggest that 1,25D3 potentially increases testosterone-induced 17beta-estradiol secretion by regulating aromatase phosphotyrosine levels, and calcium increase is involved in both 1,25D3 and testosterone-induced 17beta-estradiol secretion. 1,25D3 reverses the inhibitory effect of testosterone on Cx43 expression in granulosa cells. ///////////////////////// Vitamin d normalizes abnormally elevated serum antim?an hormone levels usually noted in women with polycystic ovary syndrome. Irani M 2014 et al. INTRODUCTION Antim?an hormone is abnormally elevated in the serum of women with polycystic ovary syndrome (PCOS). Elevated antim?an hormone in PCOS plays a key role in ovulatory dysfunction. The epidemic of vitamin D deficiency affects reproductive potential. Vitamin D3 therapy has been suggested to improve the metabolic disturbances observed in women with PCOS. We hypothesized that vitamin D3 supplementation improves follicular health in vitamin D-deficient women with PCOS, as reflected by normalization of the abnormally elevated antim?an hormone serum levels. METHODS Fifty-seven women without PCOS and 20 with PCOS diagnosed with vitamin D deficiency (less than 20 ng/mL) were either treated with 50,000 IU of vitamin D3 once weekly for 8 weeks (n=16 PCOS, 45 non-PCOS) or not treated (n=4 PCOS, 12 non-PCOS). Serum 25-hydroxyvitamin D (ng/mL) and antim?an hormone concentrations (ng/mL) were measured before and after 8 weeks of supplementation in the treated group and 8 weeks apart in the control group. Paired t test and Wilcoxon signed rank test were used as appropriate. RESULTS Compared with women in a control group, antim?an hormone concentration of women with PCOS significantly dropped after vitamin D3 supplementation (from 5.3?0.6 to 3.9?0.5, P=.003). Vitamin D3 supplementation did not alter antim?an hormone levels in non-PCOS women (P=.6). All participants showed a negative correlation between age and antim?an hormone (P<.05). As the body mass index of participants increased, there was a smaller elevation in serum 25-hydroxyvitamin D after supplementation (P<.05). CONCLUSION In vitamin D-deficient women with PCOS, appropriate vitamin D3 supplementation seems to improve follicular development and ovarian health as reflected by normalization of serum antim?an hormone. Additionally, obese women require higher doses of vitamin D3 supplementation. Funding provided by the Maimonides Research and Development Foundation. ///////////////////////// Vitamin D Alters Genes Involved in Follicular Development and Steroidogenesis in Human Cumulus Granulosa Cells. Merhi Z 2014 et al. Context: Vitamin D deficiency is common among reproductive-aged women and has a role in female reproduction. Objective: This study evaluated the role of 1,25-dihydroxyvitamin D3 (vit D3) in ovarian follicular development and steroidogenesis by using a human granulosa cell (GC) model. Design, setting and participants: 54 women who underwent IVF were enrolled. Intervention: Follicular fluid (FF), mural and cumulus GCs were collected from small (SF) and large follicles (LF). In separate experiments, primary cumulus GCs were cultured with or without vit D3 followed by RT-PCR for mRNA expression levels. The effect of recombinant anti-Mullerian hormone (AMH) on nuclear localization of phospho-Smad 1/5/8 was evaluated in the presence or absence of vit D3 by using immunofluorescence. 25 hydroxy-vitamin D (25 OH-D) levels in FF as well as cell culture media AMH, progesterone (P4), and estradiol (E2) concentrations were determined by ELISA and RIA. Main outcome measures: 1) mRNA expression levels; 2) 3-?SD enzyme activity; 3) FSH-induced aromatase mRNA and E2 production, and 3) nuclear localization of phospho-Smad 1/5/8. Results: In multivariate analysis, 25 OH-D levels in FF negatively correlated with AMH and AMHR-II mRNA levels in cumulus GCs of SF. Compared to women with replete 25 OH-D levels in FF, those with insufficient/deficient levels had a two-fold increase in AMHR-II mRNA levels in cumulus GCs of SF (p=0.02). Treatment with vit D3 caused a decrease in AMHR-II and FSHR mRNA but an increase in 3-?SD mRNA levels compared to control (p<0.05). Vit D3 enhanced 3-?SD enzyme activity as assessed by increasing P4 release; however, vit D3 did not affect FSH-induced aromatase mRNA and E2 production and it decreased the phosphorylation of Smad 1/5/8 and its nuclear localization. Conclusion: These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation. ///////////////////////// Effect of 1a,25-dihydroxyvitamin D3 on progesterone secretion by porcine ovarian granulosa cells. Smolikova K 2013 et al. The essential role of vitamin D (VD) in bone metabolism and mineral homeostasis is well established knowledge. Research indicates that classical and non-classical pathways of VD affect also cell proliferation and differentiation, the immune system, infection, and cancer. VD receptor (VDR) and VD metabolizing enzymes have been detected in female reproductive tissues, such as ovary, uterus and placenta. The presence of VD metabolites was demonstrated in follicular fluid (FF) in women undergoing in vitro fertilization and embryo transfer (IVF-ET). The recent studies show that VD regulates the expression of a?large number of genes in reproductive tissues implicating a?role for VD in female reproduction and pregnancy outcomes. There is increasing human and animal data suggesting that VD status may be associated with impaired fertility, endometriosis, polycystic ovary syndrome (PCOS), and ovarian cancer. The presence of VDR in both animal and human ovarian tissue has raised the question of a?possible direct role for 1a,25-dihydroxyvitamin D 1a,25(OH)2D3 in the regulation of steroid hormone synthesis and secretion. Our recent data have demonstrated that 1a,25(OH)2D3 may affect in vitro insulin- and follicle-stimulating hormone (FSH)-induced progesterone secretion by porcine ovarian granulosa cells. The molecular mechanisms of this action should be further investigated. Keywords: vitamin D, female reproduction, ovary, progesterone, granulosa cells. ///////////////////////// Vitamin D Regulates Anti-Mullerian Hormone Expression in Granulosa Cells of the Hen. Wojtusik J et al. Anti-Mullerian hormone (AMH) is involved in the regression of the Mullerian ducts in mammalian and avian male embryos as well as the right oviduct in avian female embryos. AMH is expressed by granulosa cells of adult hens and mammals and is thought to be involved in the recruitment of follicles from the primordial pool as well as in regulating FSH sensitivity. We have shown that AMH expression by the granulosa layer of hens is high in the small follicles, but decreased in the larger hierarchical follicles. The decline in expression of AMH with increasing follicle size is associated with an increase in expression of the receptor for FSH (FSHR) in the granulosa layer, although the mechanism is not known. In this study, we tested if vitamin D (1, 25-dihydroxyvitamin D3) regulates expression of AMH mRNA in granulosa cells of the hen. Granulosa cell layers were removed from follicles 3-5mm and 6-8mm in size, dispersed and cultured for 24 h in M199 + 5% FBS (n = 7). The medium was removed and replaced with M199 + 0.1% BSA and vitamin D (at doses of 0, 10, 100 nM) and cultured for 24 h. Cells were harvested and RNA was extracted for use in quantitative PCR. Parallel 96-well plates were set up to examine cell proliferation. AMH and FSHR mRNA expression were evaluated and all values were standardized to 18S reactions. There was a significant (P < 0.05) dose-related decrease in the expression of AMH mRNA in granulosa cells from 3-5mm and 6-8mm follicles in response to vitamin D. Additionally, FSHR mRNA and cell proliferation were significantly (P < 0.05) increased by vitamin D in both groups. Western blot analysis for the vitamin D receptor (VDR) showed doublet bands at the expected size (58 and 60 kDa) in protein isolated from the chicken granulosa layer. Immunohistochemistry was used to identify VDR within the follicle and it predominantly localized to the nucleus of granulosa cells. VDR mRNA expression in the granulosa layer, relative to follicle development, was (n = 4) increased (P < 0.05) with follicle development with greatest expression in the F1 follicle. There was no evidence for expression (mRNA or protein) of the calcium binding protein, calbindin (CALB1), in the ovary or granulosa layer. Overall, these results suggest that Vitamin D regulates AMH expression and thereby, may influence follicle selection in the hen. | ||||
| Expression regulated by | |||||
| Comment | |||||
| Ovarian localization | Cumulus, Granulosa, Theca, Luteal cells, Stromal cells, Surface epithelium | ||||
| Comment | Johnson JA, et al. reported immunohistochemical detection and distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR) in rat reproductive tissues. In the ovary, immunostaining for VDR was seen in ovarian follicles, specifically in granulosa cells. Weaker VDR immunostaining was observed in follicular thecal cells and in the ovarian stroma and germinal epithelium. Corpus luteal cells stained intensely for VDR. Expression of prostaglandin metabolising enzymes COX-2 and 15-PGDH and VDR in human granulosa cells. Thill M et al. BACKGROUND: Prostaglandins (PGs) within the periovulatory follicle are essential for various female reproductive functions such as follicular development and maturation. In animal models, granulosa cells express the PG synthesizing enzyme cyclooxygenase-2 (COX-2) and the PG inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). First references suggest a correlation between vitamin D and prostaglandin metabolism through the impact of 1,25(OH)2D3 (calcitriol) on the expression of COX-2 and 15-PGDH. MATERIALS AND METHODS: The expression of COX-2, 15-PGDH and the vitamin D receptor (VDR) in human granulosa cells (COV434, hGC and HGL5), which were originally isolated from different stages of follicular maturation, was determined by real-time PCR (RT-PCR) and Western blot analysis. RESULTS: A positive correlation of COX-2 and VDR protein was found in the COV434 and HGL5 cells and an inverse correlation of 15-PGDH and VDR protein levels in all the investigated cell types. CONCLUSION: There may be a link between VDR, associated target genes and prostaglandin metabolism in human follicular maturation and luteolysis. | ||||
| Follicle stages | |||||
| Comment | Expression profiling of vitamin D receptor in placenta, decidua and ovary of pregnant mice. Shahbazi M et al. OBJECTIVES: The presence of vitamin D receptor (VDR) and the identification of localized vitamin D3 synthesis in placenta and decidua implicate the importance of vitamin D3 in reproductive function. There is, however, no data on the expression profile of VDR in the mouse placenta and endometrium throughout the pregnancy period. STUDY DESIGN: In the present work expression of VDR in reproductive tissues of pregnant mice at different gestational phases has been addressed. Expression of VDR was determined by semi-quantitative RT-PCR, Western blotting and immunohistochemistry. RESULTS: The results showed that VDR mRNA and protein were expressed in decidua, placenta and ovary throughout the pregnancy. VDR gene expression in placenta was significantly elevated in late pregnancy when compared to that of mid pregnancy. Additionally, VDR expression level in decidua rose significantly as pregnancy progressed from early to mid stages. VDR expression in decidua of pregnant mice was higher in comparison to endometrium of non-pregnant mice. Immunohistochemical analysis revealed that VDR protein is consistently expressed by luminal and glandular epithelial cells of decidua, giant cells, glycogen rich cells and labyrinth cells of placenta and by almost all follicular cell types of ovary. Surveying the expression of VDR at the protein level by Western blotting confirmed PCR results. CONCLUSION: It seems that expression of VDR in reproductive organs is finely tuned during pregnancy indicating its eminent role in reproductive biology. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
||||
| Mutations |
8 mutations
Species: mouse
Species: human
Species: human
Species: human
Species: human
Species: human
Species: human
Species: human
|
||||
| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
|
| created: | Feb. 29, 2000, midnight | by: |
hsueh email:
home page: |
| last update: | March 22, 2020, 8:54 a.m. | by: | hsueh email: |
Click here to return to gene search form