| nuclear receptor subfamily 5 group A member 2 | OKDB#: 1085 |
| Symbols: | NR5A2 | Species: | human | ||
| Synonyms: | B1F, CPF, FTF, B1F2, LRH1, LRH-1, FTZ-F1, hB1F-2, FTZ-F1beta | Locus: | 1q32.1 in Homo sapiens | HPMR |
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| General Comment |
Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Wang S et al. (2020) Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders. THIS GENE IS A MARKER FOR GRANULOSA CELLS//////////////////
By means of yeast one-hybrid screening of a liver cDNA library, Li et al. (1998) cloned a cDNA encoding a novel hepatocyte transcription factor, which they called HB1F for human B1-binding factor. The deduced 495-amino acid protein, which has a molecular mass of 54 kD, belongs to the fushi tarazu factor-1 (FTZ-F1) subfamily of orphan nuclear receptors and is closely related to steroidogenic factor-1 (SF1), another member of this subfamily. HB1F contains a DNA-binding domain with 2 zinc finger motifs, an FTZ-F1 box, and a ligand-binding domain.
NCBI Summary: The protein encoded by this gene is a DNA-binding zinc finger transcription factor and is a member of the fushi tarazu factor-1 subfamily of orphan nuclear receptors. The encoded protein is involved in the expression of genes for hepatitis B virus and cholesterol biosynthesis, and may be an important regulator of embryonic development. [provided by RefSeq, Jun 2016] |
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| General function | Receptor, Nucleic acid binding, DNA binding, Transcription factor | ||||
| Comment | The scavenger receptor class B type I (SR-BI), which mediates selective cellular cholesterol uptake from high-density lipoproteins (HDLs), plays a key role in reverse cholesterol transport. Schoonjans K, et al 2002 reported that the orphan nuclear receptor liver receptor homolog 1 (LRH-1) and SR-BI are co-expressed in liver and ovary, suggesting that LRH-1 might control the expression of SR-BI in these tissues. LRH-1 induces human and mouse SR-BI promoter activity by binding to an LRH-1 response element in the promoter. Retroviral expression of LRH-1 robustly induces SR-BI, an effect associated with histone H3 acetylation on the SR-BI promoter. The decrease in SR-BI mRNA levels in livers of LRH-1(+/-) animals provides in vivo evidence that LRH-1 regulates SR-BI expression. Our data demonstrate that SR-BI is an LRH-1 target gene and underscore the pivotal role of LRH-1 in reverse cholesterol transport. | ||||
| Cellular localization | Nuclear | ||||
| Comment | oxyz/////////////LRH-1 high expression in the ovarian granulosa cells of PCOS patients. Yang X et al. (2021) Polycystic ovary syndrome (PCOS) is considered one of the most common endocrine disorders with heterogeneity. There are also reports that liver receptor homolog 1 [LRH-1 or nuclear receptor subfamily 5 group A member 2] plays an important role in the reproductive system. But up to now, there are no reports related to the link with PCOS and LRH-1. In this study, we aimed to detect the LRH-1 expression in the ovarian granulosa cell (GC) of PCOS patients and explore the potential relationship between LRH-1 and PCOS. In all, 146 follicular fluid samples were collected in this study, including 72 from PCOS patients and 74 from control patients who underwent intracytoplasmic sperm injection or in vitro fertilization-embryo transfer. The ovarian GCs were extracted from the patient's follicular fluid by magnetic-activated cell sorting method, and real-time quantitative PCR was used to measure the expression of LRH-1 in ovarian GCs. Then we analyzed the correlation between the expression level of LRH-1 and the clinical characteristics of the patient by using Pearson Correlation analysis. The expression of LRH-1 was significantly higher in PCOS patients ovarian GCs than that in the control patients [(1.38 ± 0.47) vs (1.03 ± 0.32), t = 5.327, p < 0.0001], and it was positively correlated with antral follicles counting (r = 0.3607, p < 0.0001) and the serum anti-Mullerian hormone (r = 0.2662, p = 0.0012), luteotropic hormone (r = 0.2518, p = 0.0022), testosterone (r = 0.2794, p = 0.0006) in all patients. No statistical significance between LRH-1 and body mass index, follicle-stimulating hormone, homeostasis model assessment of insulin resistance, dehydroepiandrosterone sulfate, progesterone. Compared with the control group, we found that LRH-1 was highly expressed in the ovarian GCs of PCOS patients. Our study has revealed the relationship between the LRH-1 expression and PCOS, which suggested that LRH-1 may play an important role in ovulation disorders. While this finding provided new ideas for the study of pathogenesis, it also provided a theoretical basis for the clinical diagnosis and treatment for PCOS.////////////////// | ||||
| Ovarian function | Follicle development, Initiation of primordial follicle growth, Cumulus expansion, Ovulation, Steroid metabolism, Luteinization, Early embryo development, pluripotency | ||||
| Comment | A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation. Meinsohn MC et al. (2021) Liver receptor homolog-1 (NR5A2) is expressed specifically in granulosa cells of developing ovarian follicles where it regulates the late stages of follicle development and ovulation. To establish its effects earlier in the trajectory of follicular development, NR5A2 was depleted from granulosa cells of murine primordial and primary follicles. Follicle populations were enumerated in neonates at postnatal day 4 (PND4) coinciding with the end of the formation of the primordial follicle pool. The frequency of primordial follicles in PND4 conditional knockout (cKO) ovaries was greater and primary follicles were substantially fewer relative to control (CON) counterparts. Ten-day in vitro culture of PND4 ovaries recapitulated in vivo findings and indicated that CON mice developed primary follicles in the ovarian medulla to a greater extent than did cKO animals. Two subsets of primordial follicles were observed in wildtype ovaries: one that expressed NR5A2 and the second in which the transcript was absent. Neither expressed the mitotic marker. KI-67, indicating their developmental quiescence. RNA sequencing on PND4 demonstrated that loss of NR5A2 induced changes in 432 transcripts, including quiescence markers, inhibitors of follicle activation, and regulators of cellular migration and epithelial-to-mesenchymal transition. These experiments suggest that NR5A2 expression poises primordial follicles for entry into the developing pool.////////////////// NR5A2 and potential regulatory miRNAs in the bovine CL during early pregnancy. Hughes CHK et al. (2020) Progesterone, which is secreted from the corpus luteum, is indispensable for the establishment and maintenance of pregnancy. The orphan nuclear receptor subfamily 5 group A member 2 (NR5A2) is a regulator of murine luteinization, but neither its regulation nor its role in the fully differentiated, mature corpus luteum (CL) have been described. Therefore, the goal of this study was to profile abundance and investigate regulation and functions of NR5A2 in the bovine CL. Treatment of cultured luteal steroidogenic cells with a pharmacological inhibitor of NR5A2 decreased progesterone production and tended to decrease abundance of HSD3B1 mRNA. Luteal NR5A2 mRNA increased and NR5A2 protein tended to increase between day 4 and day 6 of the estrous cycle, coincident with increased steroidogenic capacity of the CL. Luteal NR5A2 mRNA decreased by 8 hr after prostaglandin (PG) F2A injection. During early pregnancy, luteal NR5A2 mRNA was less on days 20 and 23 compared to day 14, but protein abundance did not change. Neither 1 nor 10 ng/mL interferon tau (IFNT) altered NR5A2 abundance in cultured luteal steroidogenic cells, but 10 ng/mL PGF2A decreased NR5A2. Because of discrepancies between mRNA and protein abundance of NR5A2, regulation by miRNA that changed during early pregnancy was investigated. miR-27b-3p, miR-432-5p, and miR-369-3p mimics decreased NR5A2 protein abundance and miR-369-3p also inhibited progesterone production. Overall, results of this study show that NR5A2 may be maintained by miRNA during early pregnancy and may be an important regulator of luteal progesterone production.//////////////////Suppression of Notch Signaling Stimulates Progesterone Synthesis by Enhancing the Expression of NR5A2 and NR2F2 in Porcine Granulosa Cells. Guo R et al. (2020) The conserved Notch pathway is reported to be involved in progesterone synthesis and secretion; however, the exact effects remain controversial. To determine the role and potential mechanisms of the Notch signaling pathway in progesterone biosynthesis in porcine granulosa cells (pGCs), we first used a pharmacological γ-secretase inhibitor, N-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl ester (DAPT), to block the Notch pathway in cultured pGCs and then evaluated the expression of genes in the progesterone biosynthesis pathway and key transcription factors (TFs) regulating steroidogenesis. We found that DAPT dose- and time-dependently increased progesterone secretion. The expression of steroidogenic proteins NPC1 and StAR and two TFs, NR5A2 and NR2F2, was significantly upregulated, while the expression of HSD3B was significantly downregulated. Furthermore, knockdown of both NR5A2 and NR2F2 with specific siRNAs blocked the upregulatory effects of DAPT on progesterone secretion and reversed the effects of DAPT on the expression of NPC1, StAR, and HSD3B. Moreover, knockdown of NR5A2 and NR2F2 stimulated the expression of Notch3. In conclusion, the inhibition of Notch signaling stimulated progesterone secretion by enhancing the expression of NPC1 and StAR, and the two TFs NR5A2 and NR2F2 acted as downstream TFs of Notch signaling in regulating progesterone synthesis.////////////////// The Ovulatory Signal Precipitates LRH-1 Transcriptional Switching Mediated by Differential Chromatin Accessibility. Bianco S et al. (2019) In the ovary, follicular growth and maturation are complicated processes that involve a series of morphological and physiological changes in oocytes and somatic cells leading to ovulation and luteinization, essential processes for fertility. Given the complexity of ovulation, characterization of genome-wide regulatory elements is essential to understand the mechanisms governing the expression of specific genes in the rapidly differentiating follicle. We therefore employed a systems biology approach to determine global transcriptional mechanisms during the early stages of the ovulatory process. We demonstrate that, following the hormonal signal that initiates ovulation, granulosa cells undergo major modification of distal regulatory elements, which coincides with cistrome reprogramming of the indispensable orphan nuclear receptor liver receptor homolog-1 ,LRH-1. This cistromic reorganization correlates with the extensive changes in gene expression in granulosa cells leading to ovulation. Together, our study yields a highly detailed transcriptional map delineating ovarian cell differentiation during the initiation of ovulation.////////////////// The Orphan Nuclear Receptor Liver Homolog Receptor-1 (Nr5a2) Regulates Ovarian Granulosa Cell Proliferation. Meinsohn MC et al. (2018) In mouse ovaries, liver receptor homolog-1, nuclear receptor subfamily 5, group A, member 2 (Nr5a2) expression is restricted to granulosa cells. Mice with Nr5a2 depletion in this cell population fail to ovulate. To determine whether Nr5a2 is essential for granulosa cell proliferation during follicular maturation, we generated granulosa-specific conditional knockout mice (genotype Nr5a2 floxed Cre-recombinase driven by the anti-Müllerian type II receptor, hereafter cKO) with Nr5a2 depletion from primary follicles forward. Proliferation in cKO granulosa cells was substantially reduced relative to control (CON) counterparts, as assessed by bromodeoxyuridine incorporation, proliferative cell nuclear antigen expression, and fluorescent-activated cell sorting. Microarray analysis revealed >2000 differentially regulated transcripts between cKO and CON granulosa cells. Major gene ontology pathways disrupted were proliferation, steroid biosynthesis, female gamete formation, and ovulatory cycle. Transcripts for key cell-cycle genes, including Ccnd1, Ccnd2, Ccne1, Ccne2, E2f1, and E2f2, were in reduced abundance. Transcripts from other cell-cycle-related factors, including Cdh2, Plagl1, Cdkn1a, Prkar2b, Gstm1, Cdk7, and Pts, were overexpressed. Although the follicle-stimulating hormone and estrogen receptors were overexpressed in the cKO animals, in vivo treatment with estradiol-17β failed to rescue decreased proliferation. In vitro inactivation of Nr5a2 using the ML180 reverse agonist similarly decreased cell-cycle-related gene transcripts and downstream targets, as in cKO mice. Pharmacological inhibition of β-catenin, an Nr5a2 cofactor, decreased cyclin gene transcripts and downstream targets. Terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling immunofluorescence and quantitative polymerase chain reaction of pro/antiapoptotic and autophagic markers showed no differences between cKO and CON granulosa cells. Thus, Nr5a2 is essential for granulosa cell proliferation, but its depletion does not alter the frequency of apoptosis nor autophagy.////////////////// The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Heng JC et al. Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) with the introduction of Oct4, Sox2, Klf4, and c-Myc. Among these four factors, Oct4 is critical in inducing pluripotency because no transcription factor can substitute for Oct4, whereas Sox2, Klf4, and c-Myc can be replaced by other factors. Here we show that the orphan nuclear receptor Nr5a2 (also known as Lrh-1) can replace Oct4 in the derivation of iPSCs from mouse somatic cells, and it can also enhance reprogramming efficiency. Sumoylation mutants of Nr5a2 with enhanced transcriptional activity can further increase reprogramming efficiency. Genome-wide location analysis reveals that Nr5a2 shares many common gene targets with Sox2 and Klf4, which suggests that the transcription factor trio works in concert to mediate reprogramming. We also show that Nr5a2 works in part through activating Nanog. Together, we show that unrelated transcription factors can replace Oct4 and uncovers an exogenous Oct4-free reprogramming code. Falender AE, et al 2003 reported the differential Expression of Steroidogenic Factor-1 and FTF/LRH-1 in the Rodent Ovary. Steroidogenic factor-1 (SF-1) (NR5A1) is an orphan nuclear receptor that plays a premier role in ovarian organogenesis. Recent studies document mRNA expression of the structurally related factor NR5A2 (FTF, LRH-1, SF-2) in the adult ovary and more specifically in granulosa cells and luteal cells but not theca cells. Conversely, SF-1 was shown to be expressed at higher levels in theca/interstitial cells. These latter observations raised the possibility that FTF/LRH-1 may control target gene expression in granulosa cells of developing follicles. Using quantitative PCR our results show that FTF/LRH-1 message is expressed at higher levels in the ovary than in liver or other tissues analyzed. We show by in situ hybridization and LacZ expression in ovaries of transgenic mice bearing an FTF-promoter-LacZ fusion gene that FTF/LRH-1 is selectively expressed in granulosa cells of rat and mouse ovaries and is not present in theca cells or interstitial cells. However, by a variety of approaches, we showed that SF-1 mRNA and protein are expressed in greater amounts than FTF/LRH-1 in granulosa cells of follicles at all stages of development. Expression of SF-1 mRNA and protein in granulosa cells was verified by in situ hybridization, immunohistochemistry of ovarian sections, and immunocytochemistry of cultured rat granulosa cells. The significance of SF-1 in regulating target gene activation was supported by EMSA. An abundant granulosa cell protein binding to the SF-1-binding motif (CCAAGGTCA) present in the aromatase promoter and an FTF/LRH-1 motif (TGTCCTTGAACA) in the alpha-fetoprotein promoter was supershifted by two SF-1-specific antibodies but not by an FTF antibody. Conversely, with the same probes, a less abundant protein/DNA complex present in liver and ovarian cell extracts was shifted by an FTF antibody but not by the SF-1 antibodies. SF-1 and FTF/LRH-1 were differentially regulated in vivo by estradiol, FSH and prolactin. Collectively these data indicate that granulosa cells of small and preovulatory follicles express both SF-1 and FTF/LRH-1 and that each orphan receptor may regulate target gene expression in these cells. Saxena D, et al reported that Liver Receptor Homolog-1 (LRH-1) Stimulates the Progesterone Biosynthetic Pathway During Follicle Stimulating Hormone (FSH)-Induced Granulosa Cell Differentiation. FSH-stimulated granulosa cell differentiation is associated with the induction of the LH receptor as well as induction of the estrogen and progesterone biosynthetic pathways. While activation of the cAMP-protein kinase A (PKA) pathway is sufficient to stimulate progesterone production, additional pathways are required for the induction of the LH receptor and P450 aromatase. The orphan nuclear receptor LRH-1 is expressed in granulosa cells and has been shown to synergize with the cAMP signaling system to regulate the gonadal type II aromatase promoter in transient transfection assays. To determine if LRH-1 can interact with the cAMP pathway in the induction of aromatase and the LH receptor, the authors examined the effects of an adenoviral vector that directs the expression of human LRH-1 (Ad-LRH-1) on FSH-stimulated granulosa cell differentiation. Infection of undifferentiated granulosa cells with LRH-1 alone had no effect on estrogen production, progesterone production or the expression of the LH receptor. However, combination of FSH stimulation and Ad-LRH-1 infection led to significantly greater progesterone production and increases in mRNA for P450scc and 3beta-HSD than granulosa cells stimulated by FSH alone. However, infection with Ad-LRH-1 did not stimulate estradiol production or increases in mRNA for P450aromatase or the LH receptor above that seen with FSH treatment alone. Moreover, infection with Ad-LRH-1 was able to overcome H-89 inhibition of FSH-stimulated progesterone but not estrogen production. Collectively, these observations support a direct role for LRH-1 in the induction of the progesterone but not the estrogen biosynthetic pathway during granulosa cell differentiation. Switching of NR5A Proteins Associated with the Inhibin {alpha}-Subunit Gene Promoter Following Activation of the Gene in Granulosa Cells Weck J, et al . The inhibin alpha-subunit gene is transcriptionally activated by FSH (FSH) in ovarian granulosa cells during follicular growth. We have investigated the roles of the NR5A family nuclear receptors SF-1 and LRH-1 in transcriptional activation of the inhibin alpha-subunit gene. Transfection assays using an inhibin alpha-subunit promoter reporter in GRMO2 granulosa cells show that LRH-1 and SF-1 act similarly to increase promoter activity, and that the activity of both transcription factors is augmented by the co-activators CBP and SRC-1. However, chromatin immunoprecipitation (ChIP) experiments illustrate differential dynamic association of LRH-1 and SF-1 with the alpha subunit inhibin promoter in both primary cells and the GRMO2 granulosa cell line such that hormonal stimulation of transcription results in an apparent replacement of SF-1 with LRH-1. Transcriptional stimulation of the inhibin alpha-subunit gene is dependent on MEK activity, as is the dynamic association/disassociation of SF-1 and LRH-1 with the promoter. Inhibition of the PI3K signaling pathway influences promoter occupancy and transcriptional activation by SF-1 but not LRH-1, suggesting a possible mechanistic basis for the distinct functions of these NR5A proteins in inhibin alpha-subunit gene regulation. Liver Receptor Homolog-1 (LRH-1) and Steroidogenic Factor-1 (SF-1) Have Similar Actions on Rat Granulosa Cell Steroidogenesis. Saxena D et al. Granulosa cells express the closely related orphan nuclear receptors steroidogenic factor-1 (SF-1) and liver receptor homolog-1 (LRH-1). To determine if SF-1 and LRH-1 have differential effects on steroid production, we compared the effects of overexpressing LRH-1 and SF-1 on estrogen and progesterone production by undifferentiated rat granulosa cells. Adenovirus mediated overexpression of LRH-1 or SF-1 had qualitatively similar effects. Neither LRH-1 nor SF-1 alone stimulated estrogen or progesterone production, but when combined with follicle stimulating hormone (FSH) and testosterone, each significantly augmented progesterone production and mRNAs for cholesterol side chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) above that observed with FSH alone, with SF-1 being more effective than LRH-1. LRH-1 did not augment FSH-stimulated estrogen production while SF-1 produced only a slight (approx. 30%) augmentation of FSH-stimulated estrogen production. The stimulatory actions of both were reduced by overexpression of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1). Expression of either LRH-1 or SF-1 together with constitutively active protein kinase B (PKB) in the absence of FSH stimulated progesterone production and mRNAs for 3beta-HSD and P450scc but did not stimulate estrogen production or mRNA for aromatase (P450arom). These findings demonstrate that LRH-1 and SF-1 have qualitatively similar actions on FSH-stimulated estrogen and progesterone production which would suggest that these factors may have overlapping actions in the regulation of steroidogenesis that accompanies granulosa cell differentiation. | ||||
| Expression regulated by | LH, Steroids, SF1 | ||||
| Comment | A Novel Isoform of Liver Receptor Homolog-1 Is Regulated by Steroidogenic Factor-1 and the Specificity Protein Family in Ovarian Granulosa Cells. Kawabe S et al. Liver receptor homolog-1 (LRH-1) is a member of the nuclear receptor 5A (NR5A) subfamily. It is expressed in granulosa cells of the ovary and is involved in steroidogenesis and ovulation. To reveal the transcriptional regulatory mechanism of LRH-1, we determined its transcription start site in the ovary using KGN cells, a human granulosa cell tumor cell line. 5'-rapid amplification of cDNA ends PCR revealed that human ovarian LRH-1 was transcribed from a novel transcription start site, termed exon 2o, located 41 bp upstream of the reported exon 2. The novel LRH-1 isoform was expressed in the human ovary but not the liver. Promoter analysis and an EMSA indicated that a steroidogenic factor-1 (SF-1) binding site and a GC box upstream of exon 2o were required for promoter activity, and that SF-1 and specificity protein (Sp)-1/3 bind to the respective regions in ovarian granulosa cells. In KGN cells, transfection of SF-1 increased ovarian LRH-1 promoter activity and SF-1-dependent reporter activity was further enhanced when peroxisome proliferator-activated receptor-? coactivator-1a (PGC-1a) was cotransfected. In Drosophila SL2 cells, Sp1 was more effective than Sp3 in enhancing promoter activity, and co-transfection of the NR5A-family synergistically increased activity. Infection with adenoviruses expressing SF-1 or PGC-1a induced LRH-1 expression in KGN cells. These results indicate that the expression of human LRH-1 is regulated in a tissue-specific manner, and that the novel promoter region is controlled by the Sp-family, NR5A-family and PGC-1a in ovarian granulosa cells in a coordinated fashion. Testosterone, not 5{alpha}-Dihydrotestosterone, Stimulates LRH-1 Leading to FSH-Independent Expression of Cyp19 and P450scc in Granulosa Cells. Wu YG et al. Androgens are crucial for normal folliculogenesis and female fertility as evidenced in androgen receptor-null and granulosa cell conditional knockout mice. It is thought, however, that the multiple effects of androgens in the ovary are mainly complementary to the actions of gonadotropins. Using primary rat granulosa cells, we demonstrated that in the absence of gonadotropins, testosterone (T) increases aromatase (Cyp19) and P450 side-change cleavage expression, two enzymes crucial for normal ovarian function. T can be converted into estradiol, a classical estrogen, by Cyp19 and into 5a-dihydrotestosterone, a pure androgen, by 5a-reductase. However, inhibition of Cyp19 and/or 5a-reductase did not prevent the stimulatory effects of T. In contrast, the effect of this steroid was potentiated by blocking 5a-reductase. Additionally, T, not 5a-dihydrotestosterone, stimulates liver receptor homolog-1 (LRH-1) expression, whereas the expression of steroidogenic factor-1 (SF-1) was not affected by either steroid. LRH-1 and SF-1 are transcription factors known to be involved in the regulation of Cyp19. Accordingly, small interference RNA against LRH-1 prevented Cyp19 and P450 side-change cleavage up-regulation whereas anti-SF-1 small interference RNA had no effects. Chromatin immunoprecipitation demonstrated that T stimulation of LRH-1 leads to the recruitment of LRH-1 to the native Cyp19 promoter, which was not affected by cotreatment with 5a-reductase and Cyp19 inhibitors. Finally, gel shift and supershift analysis demonstrated that the androgen receptor binds to an androgen response element located within the LRH-1 promoter. These results provide novel evidence that T has a direct effect on the expression of genes involved in granulosa cell differentiation. NURSA Molecule Pages: NURSA Molecule Pages: Nuclear Receptors: SF-1 | LRH-1 | GR Ligands: Testosterone | Dihydrotestosterone. Peng N, et al reported the Role of the Orphan Nuclear Receptor, Liver Receptor Homologue-1, in the Regulation of Human Corpus Luteum 3beta-Hydroxysteroid Dehydrogenase Type II. After ovulation, ovarian 3beta-hydroxysteroid dehydrogenase type II (HSD3B2) expression increases to enhance the shift of steroidogenesis toward progesterone biosynthesis. Steroidogenic factor-1 (SF-1) is a transcription factor for several genes encoding steroidogenic enzymes. However, the level of SF-1 expression decreases in the human corpus luteum (CL) after ovulation. Liver receptor homolog-1 (LRH-1) is another member of the orphan nuclear receptor family. We hypothesize that LRH-1, rather than SF-1, plays an essential role in the regulation of corpus luteum steroidogenesis. Semiquantitative RT-PCR and real-time PCR were performed to quantify the level of LRH-1 expression and correlate with HSD3B2 level. Cell transfection, mutation analysis, and EMSA were performed to examine the role of LRH-1 in the regulation of HSD3B2. LRH-1 expression was higher in CL, compared with mature ovarian follicles. Cotransfection of granulosa cells with HSD3B2 and LRH-1 resulted in a 10-fold increase of transcription. DAX-1 inhibited LRH-1-stimulated HSD3B2, which was maintained in the presence of dibutyryl cAMP. Mutation of the either of the two putative LRH-1 binding sites, which were confirmed by EMSA, in the HSD3B2 promoter decreased LRH-1 stimulation. Our findings suggest that LRH-1 is highly expressed in CL, and it plays an essential role in the regulation of HSD3B2. The Orphan Nuclear Receptor, Liver Receptor Homologue-1, Regulates Cholesterol Side-Chain Cleavage Cytochrome P450 Enzyme in Human Granulosa Cells Kim JW,et al . Following ovulation, there is a shift in ovarian steroidogenesis from an estrogen producing ovarian follicle to a progesterone producing corpus luteum. The first step in human ovarian steroidogenesis is catalyzed by cholesterol side chain cleavage cytochrome P450 (CYP11A1) enzyme. Steroidogenic factor-1 (SF-1) is an orphan nuclear receptor that regulates several steroidogenic enzymes, including CYP11A1. Liver receptor homolog-1 (LRH-1) is another orphan nuclear receptor that is expressed in the human ovary. Following ovulation there is a down-regulation in SF-1, which is associated with an up-regulation of LRH-1 expression. These changes coincide with increased level of CYP11A1 expression in human corpus luteum. In this study, we examined the role of LRH-1 in the regulation of human granulosa cell CYP11A1 expression. Co-transfection of human granulosa cell tumor cells with CYP11A1 promoter and LRH-1 expression vector resulted in a significant increase in CYP11A1 expression. Deletion analysis revealed two putative LRH-1 binding sites at -1580 and -40, which was confirmed by EMSA. DAX-1 inhibited LRH-1 stimulated CYP11A1 expression and that was not overcome by the presence of PKA agonist. We conclude that CYP11A1 expression in human granulosa cells is regulated by LRH-1. We propose that LRH-1 could be the major transcription factor for the post-ovulatory surge in human ovarian steroidogenesis. Gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function. | ||||
| Ovarian localization | Primordial Germ Cell, Oocyte, Granulosa, Luteal cells, Ovarian tumor | ||||
| Comment | Liver Receptor Homologue-1 expression in ovarian epithelial and granulosa cell tumours. Chand AL et al. Granulosa cell tumours of the ovary (GCT) express aromatase and produce oestrogens. The ovarian-specific aromatase promoter (pII) is regulated by members of the group 5A nuclear receptor family, SF-1 and LRH-1. Since both SF-1 and LRH-1 are implicated in proliferation and cancer, we hypothesised that alteration in the expression of either or both receptors may be associated with GCT. We therefore determined the expression of LRH-1, SF-1 and aromatase in a cohort of GCT, mucinous and serous cystadenocarcinomas, and normal ovaries. LRH-1 mRNA was present at low level in normal ovary and serous cystadenocarcinoma, but was elevated approximately 30-fold in GCT, and 8-fold in mucinous cystadenocarcinoma, compared to normal ovary. LRH-1 protein expression was confirmed in GCT by immunohistochemistry. SF-1 mRNA was significantly lower that of LRH-1 in all samples and not significantly altered in GCT, compared to normal ovary. Aromatase mRNA was present at low level in normal ovary and serous and mucinous cystadenocarcinoma, and significantly elevated (18-fold) in GCT compared to normal ovary. Despite the coordinate over-expression of both LRH-1 and aromatase in GCT versus normal ovary, their levels did not correlate in individual patients; rather, aromatase expression correlated with that of SF-1. Finally, although both LRH-1 and SF-1 activated aromatase promoter activity in transient transfection studies, gel-shift and chromatin immunoprecipitation data indicated that SF-1, but not LRH-1, bound to the aromatase promoter. We conclude that SF-1 regulates aromatase expression in GCT; over-expression of LRH-1 suggests that this receptor may be involved in the pathogenesis of GCT by mechanisms other than the regulation of aromatase. Its role in this disease therefore warrants further investigation. Liver receptor homolog-1 localization in the nuclear body is regulated by sumoylation and cAMP signaling in rat granulosa cells. Yang FM et al. Liver receptor homolog-1 (LRH-1; NR5A2) is an orphan member of the nuclear receptor superfamily, mainly expressed in endoderm-derived tissues and in the ovary. In ovarian granulosa and luteal cells, LRH-1 regulates the expression of genes associated with ovarian steroidogenesis. LRH-1 can be transported to transcriptionally inactive nuclear bodies after conjugation with small ubiquitin-related modifier (SUMO). In the present study, we investigated the effects of SUMO modification at five lysine residues of LRH-1 in rat granulosa cells. Lysine 289 could be conjugated with SUMO-1 in vitro, and the mutation K289R increased transcriptional activity of LRH-1, suggesting that SUMO conjugation is associated with transcription repression. Coexpression of SUMO-1 targets LRH-1 to the dot-like nuclear bodies, but the effect of lysine mutations on blocking subnuclear localization depended on the cell type. In COS-7 cells, mutation of either K173 or K289 prevented SUMO-1-mediated translocation of LRH-1 into nuclear bodies and also reduced the conjugation by SUMO-1, suggesting that K289 and K173 are two important sites involved in SUMO-1 modification. In granulosa cells, three or more altered lysine residues were required for nucleoplasm retention. This result suggests that multiple lysine residues are targets for SUMO conjugation in vivo and granulosa cells are more sensitive to SUMO-1-mediated LRH-1 localization to nuclear bodies. Nuclear body localization of LRH-1 was suppressed by forskolin and cholera toxin. Forskolin treatment obviously influences the expression of members involved in the SUMO pathway. The results obtained in the present study suggest that cAMP signaling could change the dynamic process of sumoylation and repress LRH-1 targeting to nuclear speckles in rat granulosa cells. Boerboom D, et al reported the expression and regulation of transcripts encoding two members of the NR5A nuclear receptor subfamily of orphan nuclear receptors, steroidogenic factor-1 and NR5A2, in equine ovarian cells during the ovulatory process. Steroidogenic factor-1 (SF-1, NR5A1a) is a member of the NR5A nuclear receptor subfamily and has been implicated as a key transcriptional regulator of all ovarian steroidogenic genes in vitro. The NR5A2 ORF encodes a 495-amino acid protein that is 60% identical to SF-I, including 99%-similar DNA-binding domains. Northern blot analysis revealed that SF-1 and NR5A2 were expressed in all major steroidogenic tissues, with the exception that NR5A2 was not present in the adrenal. Interestingly, NR5A2 was found to be, by far, the major NR5A subfamily member expressed in the preovulatory follicle and the corpus luteum. Using a semiquantitative RT-PCR/Southern blotting approach, the regulation of SF-1 and NR5A2 mRNAs in. vivo was studied in equine follicular cells obtained from preovulatory follicles isolated between 0 and 39 h post hCG. The granulosa cell layer was the predominant, if not the sole, site of NR5A2 mRNA expression in the follicle. Importantly, NR5A2 was much more highly expressed in granulosa cells than SF-1. The administration of hCG caused a significant decrease in NR5A2 transcripts in granulosa cells at 30, 36, and 39 h post hCG (P < 0.05). Based on the marked expression of NR5A2 in equine granulosa and luteal cells and on mounting evidence of a functional redundancy between SF-1 and NR5A2 in other species, it is proposed that NR5A2 may play a key role in the regulation of gonadal steroidogenic gene expression. Temporal and spatial expression of liver receptor homologue-1 (LRH-1) during embryogenesis suggests a potential role in gonadal development Hinshelwood MM, et al . Liver receptor homologue-1 (LRH-1), an orphan member of the nuclear receptor family highly expressed in adult mouse ovary, is closely related to steroidogenic factor 1 (SF-1), known to be important in gonadal formation. To analyze the potential role of LRH-1 in gonadal differentiation, we compared LRH-1 and SF-1 expression during mouse embryonic and postnatal development. LRH-1 expression was first detected in the urogenital ridge before sexual determination, in primordial germ cells and surrounding somatic cells; expression persisted after differentiation into testes and ovaries. Of interest, LRH-1 expression declined in the developing ovary and testis at embryonic day 15.5 but increased again just after birth in the ovary in granulosa cells and transiently in oocytes of developing follicles. By comparing and contrasting LRH and SF-1 expression with the two tissue-specific steroidogenic markers, cytochromes P450 aromatase and P450 17alpha-hydroxylase/17,20 lyase, we provide evidence for a potential role for LRH-1 in gonadal development, the initiation of folliculogenesis and regulation of estrogen biosynthesis within the ovary. Developmental Dynamics, 2005. (c) 2005 Wiley-Liss, Inc. | ||||
| Follicle stages | Antral, Preovulatory, Corpus luteum | ||||
| Comment | Liu DL, et al 2003 reported the Expression and Functional Analysis of Liver Receptor Homologue-1 as a Potential Steroidogenic Factor in Rat Ovary. Liver receptor homologue-1 (LRH-1) is a member of the nuclear receptor superfamily originally found in liver cells. LRH-1 participates in regulation of cholesterol metabolism and bile acid synthesis. Recent studies have shown that LRH-1 is even more highly expressed in ovary and LRH-1 has been implicated as a key transcriptional regulator of cytochrome P450 aromatase (P450arom) in vitro. The results showed that LRH-1 mRNA and protein were primarily localized to granulosa cells and luteinized follicles or newly formed corpora lutea (CL) of immature and adult rats, and the levels of expression increased during PMSG-hCG-induced follicular development and ovulation. In the functional CL of pregnant rats, a biphasic change in LRH-1 mRNA content occurred throughout the gestation process, whereas LRH-1 protein was persistently detected during the entire pregnancy. In the consecutive ovarian sections, expression of LRH-1 showed an approximate colocalization with that of P450arom in both tertiary and Graafian follicles and the functional CL of pregnant rats. We also found that LRH-1 mRNA and protein expression preceded P450arom during early follicular development. In conclusion, the stage-specific expression of LRH-1 in rat granulosa and luteal cells suggests a role for LRH-1 in the regulation of ovarian function. The overlapping but distinct expression patterns between LRH-1 and P450arom circumstantially support the recent finding that LRH-1 serves as a critical upstream regulator of P450arom gene expression in ovarian cells, but it should also be considered that LRH-1 may be a multifunctional steroidogenic factor in ovarian physiology. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
7 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: ovine
Species: mouse
Species: ovine
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Dec. 30, 2000, 8:43 a.m. | by: |
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| last update: | June 22, 2021, 11:54 a.m. | by: | hsueh email: |
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