| estrogen receptor 2 | OKDB#: 74 |
| Symbols: | ESR2 | Species: | human | ||
| Synonyms: | Erb, ESRB, ODG8, ESTRB, NR3A2, ER-BETA, ESR-BETA | Locus: | 14q23.2-q23.3 in Homo sapiens | HPMR |
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| General Comment |
Estrogen receptors are transcriptional factors with DNA binding domain and a ligand binding domain. Mosselman et al. (1996) identified and characterized a human estrogen receptor, which they called estrogen receptor-beta (ER-beta). ER-beta is homologous to the previously identified estrogen receptor-alpha and has an overlapping but nonidentical tissue distribution. The DNA-binding domain of ER-beta is 96% conserved compared to ER-alpha, and the ligand-binding domain shows 58% conserved residues. Northern blot analysis showed that ER-beta is expressed in human thymus, spleen, ovary, and testis.
NCBI Summary: This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008] |
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| General function | Receptor, Nucleic acid binding, DNA binding, Transcription factor | ||||
| Comment | The absence of ER results in altered gene expression in ovarian granulosa cells isolated from in vivo preovulatory follicles. Binder AK et al. Determining the spatial and temporal expression of genes involved in the ovulatory pathway is critical for the understanding of the role of each estrogen receptor in the modulation of folliculogenesis and ovulation. Estrogen receptor (ER) is highly expressed in ovarian granulosa cells and mice lacking ER (ERKO) are subfertile due to inefficient ovulation. Previous work has focused on isolated granulosa cells or cultured follicles and while informative, provides confounding results due to the heterogeneous cell types present including granulosa, theca and oocytes and exposure to in vitro conditions. Herein, we isolated preovulatory granulosa cells from WT and ER-null mice using laser capture microdissection to examine the genomic transcriptional response downstream of PMSG (mimicking FSH) and PMSG/hCG (mimicking LH) stimulation. This allows for a direct comparison of in vivo granulosa cells at the same stage of development from both WT and ER-null ovaries. ER-null granulosa cells showed altered expression of genes known to be regulated by FSH (Akap12 and Runx2) as well as not previously reported (Arnt2 and Pou5f1) in WT granulosa cells. Our analysis also identified 304 genes not previously associated with ER in granulosa cells. LH responsive genes including Abcb1b and Fam110c show reduced expression in ER-null granulosa cells; however novel genes including Rassf2 and Megf10 were also identified as being downstream of LH signaling in granulosa cells. Collectively, our data suggests that granulosa cells from ER-null ovaries may not be appropriately differentiated and are unable to respond properly to gonadotropin stimulation. Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Harris HA, et al . The discovery of a second estrogen receptor (ER), called ERbeta, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERbeta and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERbeta does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50-75%). These data suggest that one function of ERbeta may be to modulate the immune response, and that ERbeta-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation. | ||||
| Cellular localization | Nuclear | ||||
| Comment | Maternal tamoxifen treatment alters oocyte differentiation in the neonatal mice: inhibition of oocyte development and decreased folliculogenesis. Roshangar L et al. AIM: Primary germ cells after migration to the developing ovary differentiate to oogonia and oocytes. The formation and number of primordial follicles in early fetal life are determining factors in the fertility state of adult life. Tamoxifen is used both to stimulate ovulation and as an anticancer drug. The aim of the present study was to evaluate the effect of tamoxifen on oocyte and follicular development and differentiation in mice. METHODS: Thirty adult female and 15 adult male mice were used in the present study. The female mice were divided into two groups: control and experimental. Two female mice at their sterous cycle were placed with one male mouse in a cage for mating. The observation of a vaginal plug was considered the 1st day of pregnancy. On the 13th day of pregnancy the mice received 100 microg tamoxifen by i.p. injection. At the end of pregnancy 2-, 3-, 6- and 7-day-old newborns were killed and their ovaries were fixed and prepared for light and electron microscopic studies. The number of follicular nests and diameter of primordial and primary follicles were determined using Motic software (Motic Incorporation Ltd, Canada) and compared with control values using t-test. RESULTS: Microscopy and morphometry showed that oocyte nests are formed on the 2nd and 3rd days and follicles are distinguished on the 6th and 7th days. Morphometric studies revealed that the number and diameters of oocyte nests were significantly (P < 0.001) reduced in the experimental groups compared to the control group. However, the numbers and diameters of primordial and primary follicles in experiential and controls were not significantly different. Electron microscopic studies revealed that in the control group, oocytes were separated from each other and were at primordial follicle stage. However, in the experimental group, the oocytes were in clusters as oocyte nests. CONCLUSION: The results indicate that tamoxifen suppresses follicular differentiation at early stages but does not affect the development of already differentiated follicles. | ||||
| Ovarian function | Follicle endowment, Follicle development, Initiation of primordial follicle growth, Primary follicle growth, Preantral follicle growth, Antral follicle growth, Follicle atresia, Ovulation, Steroid metabolism, Luteinization, Luteolysis, Oocyte maturation | ||||
| Comment | Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro. Ting AY et al. (2015) What are the direct effects of progesterone (P4) and estradiol (E2) on the development and function of primate follicles in vitro from the pre-antral to early antral stage? In a steroid-depleted milieu, E2 improved follicle survival, growth, antrum formation and oocyte health, whereas P4 exerted minimal beneficial effects on follicle survival and reduced oocyte health. Effects of P4 and E2 on follicle development have been studied primarily in large antral and pre-ovulatory follicles. Chronic P4 exposure suppresses antral follicle growth, but acute P4 exposure promotes oocyte maturation in pre-ovulatory follicles. Effects of E2 can be stimulatory or inhibitory depending upon species, dose and duration of exposure. Non-human primate model, randomized, control versus treatment. Macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. Adult rhesus macaque secondary follicles were encapsulated in 0.25% alginate and cultured individually in media containing follicle stimulating hormone plus (i) vehicle, (ii) a steroid-synthesis inhibitor, trilostane (TRL, 250 ng/ml), (iii) TRL + low E2 (100 pg/ml) or progestin (P, 10 ng/ml R5020) and (iv) TRL + high E2 (1 ng/ml E2) or P (100 ng/ml R5020). Follicles reaching the antral stage (≥750 µm) were treated with human chorionic gonadotrophin for 34 h. End-points included follicle survival, antrum formation, growth pattern, plus oocyte health and maturation status, as well as media concentrations of P4, E2 and anti-Müllerian hormone (AMH). In a steroid-depleted milieu, low dose, but not high dose, P improved (P < 0.05) follicle survival, but had no effect (P > 0.05) on antrum formation and AMH production. Low-dose P increased (P < 0.05) P4 production in fast-grow follicles, and both doses of P elevated (P < 0.05) E2 production in slow-grow follicles. Additionally, low-dose P increased (P < 0.05) the percentage of no-grow follicles, and high-dose P promoted oocyte degeneration. In contrast, E2, in a steroid-depleted milieu, improved (P < 0.05) follicle survival, growth, antrum formation and oocyte health. E2 had no effect on P4 or E2 production. Follicles exposed to E2 yielded mature oocytes capable of fertilization and early cleavage, at a rate similar to untreated control follicles. This study is limited to in vitro effects of P and E2 during the interval from the secondary to small antral stage of macaque follicles. This study provides novel information on the direct actions of P4 and E2 on primate pre-antral follicle development. Combined with our previous report on the actions of androgens, our findings suggest that androgens appear to be a survival factor but hinder antral follicle differentiation, E2 appears to be a survival and growth factor at the pre-antral and early antral stage, whereas P4 may not be essential during early folliculogenesis in primates. NIH P50 HD071836 (NCTRI), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), ONPRC 8P51OD011092. There are no conflicts of interest.////////////////// Insufficient Luteinizing Hormone-Induced Intracellular Signaling Disrupts Ovulation in Preovulatory Follicles Lacking Estrogen Receptor-{beta} Rodriguez KF et al. Gonadotropin-stimulated estrogen receptor-beta (ERbeta)-null preovulatory follicles exhibit submaximal estradiol production, insufficient acquisition of LH receptor, and attenuated expression of essential ovulatory genes. These observations lead to low ovulatory rates compared with wild-type (WT) follicles. We hypothesize that insufficient LH receptor results in reduced cAMP production after an ovulatory stimulus. Individual preantral follicles were cultured with FSH for 4 d and then induced to ovulate with a single dose of human chorionic gonadotropin (hCG). cAMP levels 1 h after hCG were 50% lower in ERbeta-null than WT follicles. To determine whether the lack of LH receptor, and resulting lack of cAMP, could be bypassed by direct activation of adenylyl cyclase, WT and ERbeta-null follicles were induced to ovulate with forskolin. Ten micromolar forskolin doubled the ovulatory rate of ERbeta-null follicles compared with treatment with hCG ( approximately 50 vs. 25%, respectively). In WT follicles, 10 muM forskolin reduced the ovulation rate compared with hCG (14 vs. 83%, respectively), indicating that high doses of forskolin inhibited WT ovulation. A 10 muM concentration of forskolin induced cAMP levels in ERbeta-null follicles that were comparable to levels produced in WT follicles after hCG and either partially or completely rescued the attenuated expression of LH-responsive genes. These data indicate that direct activation of adenylyl cyclase, resulting in increased production of cAMP, partially rescues the ovulatory response of ERbeta-null follicles, suggesting that insufficient LH receptor and low cAMP levels contribute to their poor ovulatory rates. We also determined that ERbeta-null ovaries exhibit an alteration in the activation of MAPKp42/44. Our evaluation of the ERbeta-null ovarian phenotype indicates that ERbeta plays a role in facilitating folliculogenesis. We show that expression of ERbeta in preovulatory follicles is required for adequate cAMP production and propose that an optimal level of cAMP is required for hCG-stimulated ovulation. Differences in oocyte development and estradiol sensitivity among mouse strains. Pepling ME et al. Mouse oocytes develop in clusters of interconnected cells called germ line cysts. Shortly after birth, the majority of cysts break apart and primordial follicles form consisting of one oocyte surrounded by granulosa cells. Concurrently, oocyte number is reduced by two-thirds. Exposure of neonatal females to estrogenic compounds causes multiple oocyte follicles that are likely germ line cysts that did not break down. Supporting this idea, estrogen disrupts cyst breakdown and may regulate normal oocyte development. Previously, the CD-1 strain was used to study cyst breakdown and oocyte survival but it is unknown if there are differences in these processes in other mouse strains. It is also unknown if there are variations in estrogen sensitivity during oocyte development. Here, we examined neonatal oocyte development in FVB, C57BL/6 and F2 hybrid (Oct4-GFP) strains and compared them to the CD-1 strain. We found variability in oocyte development among the four strains. We also investigated estrogen sensitivity differences and found that C57BL/6 ovaries are more sensitive to estradiol than CD-1, FVB or Oct4-GFP strains. Insight into differences in oocyte development will facilitate comparison of mice generated on different genetic backgrounds. Understanding variations in estrogen sensitivity will lead to better understanding of risks of environmental estrogen exposure in humans. Estrogen Can Signal through Multiple Pathways to Regulate Oocyte Cyst Breakdown and Primordial Follicle Assembly in the Neonatal Mouse Ovary. Chen Y et al. During mouse embryonic development, oocytes develop in germline cysts, formed by several rounds of cell division followed by incomplete cytokinesis. Shortly after birth, cysts break down and individual oocytes are enclosed by granulosa cells to form primordial follicles. At the same time, two thirds of the oocytes die by apoptosis with only one third surviving. We have previously shown that the steroid hormones, estradiol (E2) and progesterone, as well as the phytoestrogen genistein can inhibit cyst breakdown and primordial follicle assembly. However, the mechanisms by which steroid hormones regulate oocyte cyst breakdown and selective oocyte survival are unknown. Here, we confirmed expression of estrogen receptor (ER) mRNA and protein in neonatal mouse ovaries using RT-PCR, Western blotting and immunocytochemistry. We then used estrogen receptor specific agonists and antagonists to understand the mechanism of estrogen signaling. PPT, an ERalpha selective agonist and DPN, an ERbeta selective agonist both inhibited cyst breakdown in organ culture, suggesting that E2 can signal through both receptors to regulate cyst breakdown. ICI 182,780, an estrogen receptor antagonist completely blocked E2's action. MPP, an ERalpha specific antagonist fully blocked E2's effect on oocyte cyst breakdown and primordial follicle assembly and (R,R)-THC, an ERbeta specific antagonist, partially blocked E2, further supporting the idea that both receptors are involved in estrogen signaling in neonatal oocyte development. E2 conjugated to BSA which can only exert effects at the membrane, was able to inhibit cyst breakdown, implying that E2 could also function through a membrane bound estrogen receptor to regulate cyst breakdown. Effects of Diethylstilbestrol on Programmed Oocyte Death and Induction of Polyovular Follicles in Neonatal Mouse Ovaries. Kim H et al. In mice, neonatal exposure to a synthetic estrogen, diethylstilbestrol (DES), induces polyovular follicles, which contain two or more oocytes per ovarian follicle. We previously reported that the estrogen receptor (ER) beta (ESR2) mediates DES signaling in polyovular follicle induction. However, the specific mechanism of polyovular follicle induction has not yet been clarified. Folliculogenesis in rodents begins soon after birth, accompanied by programmed oocyte death and germ cell loss. In this study, the effects of DES on oocyte death and on mRNA expression of genes thought to be involved in polyovular follicle induction were analyzed during crucial period of folliculogenesis in the ovary of C57BL/6J, Fas(lpr/lpr) (lacking cell death receptor, FAS) and Esr2 knockout (Esr2KO) mice. Neonatal DES exposure reduced programmed oocyte death in C57BL/6J mice; however, this reduction was not observed in Esr2KO mice. In control Fas(lpr/lpr) mice, the oocyte apoptotic index was significantly lower than that in the control C57BL/6J mice. However, the polyovular follicle incidence in control, 20-day-old Fas(lpr/lpr) mice was similar to that in the control C57BL/6J mice. Moreover, DES exposure changed mRNA expression of inhibin alpha (Inha) in 2-day-old C57BL/6J mice. These results suggest that inhibition of oocyte death by DES through ESR2 may be one of the triggers for polyovular follicle induction. The FAS system is also involved in neonatal oocyte death; however, reduction of oocyte death is not sufficient for polyovular follicle induction. The combination of increased Inha mRNA and reduction of oocyte death in the ovaries of mice by DES through ESR2 might be correlated with polyovular follicle induction. Estrogen receptor beta is required for optimal cAMP production in mouse granulosa cells. Deroo BJ et al. Granulosa cells of preovulatory follicles differentiate in response to Follicle Stimulating Hormone (FSH), and this differentiation is augmented by estradiol. We have previously shown that FSH-mediated granulosa cell differentiation requires functional Estrogen Receptor beta (ERbeta) by demonstrating that the granulosa cells of ERbeta(-/-) FSH-treated mice are unable to maximally induce expression of the luteinizing hormone (LH) receptor (an indicator of granulosa cell differentiation) compared to ERbeta(+/+) controls. As a result, FSH-primed ERbeta(-/-) granulosa cells exhibit a reduced response to a subsequent ovulatory dose of luteinizing hormone. In this study, we further characterized the attenuated response of ERbeta(-/-) granulosa cells to stimulation by LH and FSH using isolated mouse granulosa cells and primary granulosa cell cultures. We observed a 50% reduction in cAMP levels in cultured ERbeta(-/-) granulosa cells exposed to LH compared to ERbeta(+/+) controls. We also observed an attenuated genomic response in granulosa cells isolated from FSH-primed ERbeta(-/-) mice compared to ERbeta(+/+) controls. Our data indicate that this attenuated response may result from inadequate levels of cAMP, since cAMP levels in cultured ERbeta(-/-) granulosa cells exposed to forskolin were approximately 50% lower than in ERbeta(+/+) granulosa cells. Phosphorylation of CREB, an indicator of PKA activity, was also reduced in FSH-treated ERbeta(-/-) granulosa cells compared to ERbeta(+/+) controls. These are the first data to indicate that ERbeta plays a role in the induction of the cAMP pathway in mouse granulosa cells, and that disruption of proper ERbeta signaling associated with this pathway may cause negative effects on ovulation and fertility. Beker-Van Woudenberg AR, investigated the expression of estradiol (classical) receptor alpha (ERalpha) and beta (ERbeta) mRNA in oocytes and cumulus cells (CC) and also studied the effects of different exposure times to E2 (before and after germinal vesicle breakdown, GVBD) on nuclear maturation. To study the possible involvement of the putative estradiol plasma membrane receptor on the IVM of oocytes, we used E2 conjugated with bovine serum albumin (E2-BSA), which cannot cross the plasma membranes. Our results demonstrate that oocytes expressed ERbeta mRNA, while CC expressed both ERalpha and ERbeta mRNA. Exposure to E2 during the first 8h of culture (before GVBD) induced a block at the metaphase I stage (MI). However, the presence of E2 after GVBD induced an increase of oocytes with nuclear aberrations. Meiotic spindle organization was severely affected by E2 during IVM and multipolar spindle was the most frequently observed aberration. Exposure of oocytes to E2-BSA neither affected nuclear maturation, nor blastocyst formation rate, nor embryo quality. Our results suggest that the detrimental effects of E2 on in vitro nuclear maturation of bovine oocyte are not exerted via a plasma membrane receptor. Estrogen Receptor-{beta} Is Critical to Granulosa Cell Differentiation and the Ovulatory Response to Gonadotropins Couse JF, et al . The process of granulosa cell differentiation that occurs in preovulatory follicles is dependent on FSH but requires augmentation by estradiol. To determine which estrogen receptor (ER) form mediates the effects of estradiol during gonadotropin-induced follicle growth, differentiation, and rupture, we characterized the response of ERalpha- and ERbeta-null mice to gonadotropin-induced ovulation. Immature mice were treated with an ovulatory regimen of exogenous gonadotropins and tissues were collected at distinct time points for morphological, biochemical, gene expression, and immunohistochemical analyses. Granulosa cells of ERbeta knockout (ERKO) preovulatory follicles exhibited an attenuated response to FSH-induced differentiation, as evident by reduced aromatase activity and estradiol synthesis, and insufficient expression of LH receptor. As a result, betaERKO ovaries were unable to fully respond to an ovulatory bolus of gonadotropin, leading to a reduced rate of follicle rupture; insufficient induction of prostaglandin-synthase 2 and progesterone receptor; an aberrant increase in aromatase activity and plasma estradiol; and incomplete expansion of the cumulus-oocyte complex. Parallel characterization of alphaERKO females indicated a minimal role for ERalpha in granulosa cell differentiation, ovulation, and the concomitant changes in gene expression, although some abnormalities were revealed. These studies demonstrate that ERbeta-mediated estradiol actions are vital to FSH-induced granulosa cell differentiation; and in the absence of ERbeta, preovulatory follicles are deficient in the necessary cellular organization (i.e. antrum and cumulus oocyte complex), enzymatic activity (i.e. capacity to convert androgen precursor to estradiol), and receptor signaling pathways (i.e. LH receptor) to respond to a gonadotropin surge and expel a healthy oocyte. | ||||
| Expression regulated by | Growth Factors/ cytokines, activin | ||||
| Comment | ESR2 is essential for gonadotropin induced Kiss1 expression in granulosa cells. Chakravarthi VP et al. (2018) Hypothalamic expression of Kiss1 plays an essential role in the onset of puberty, gonadal development, and ovulation. Estrogens regulate the expression of Kiss1 in the hypothalamus through ESR1. Kiss1 is also expressed in the ovary, where its expression correlates with the onset of puberty and progression of the estrous cycle. To date, estrogen regulation of Kiss1 expression in the ovary has not been investigated. We recently observed that gonadotropin-induced Kiss1 expression was absent in Esr2-null rat ovaries even though Esr1 was present. Wildtype granulosa cells abundantly expressed Kiss1 and oocytes expressed the Kiss1 receptor. We characterized ESR2-regulation of Kiss1 expression in granulosa cells by identifying granulosa cell-specific transcript variants and potential regulatory regions. The Kiss1 promoter, an upstream enhancer and a downstream enhancer, all possessed conserved EREs and showed active histone marks in gonadotropin-stimulated granulosa cells. The transcriptionally active Kiss1 promoter, as well as the enhancers, also revealed enrichment for ESR2 binding. Furthermore, activity of a Kiss1 promoter construct was induced following overexpression of ESR2 and was blocked upon mutation of an ERE within the promoter. Finally, PMSG and hCG administration induced phosphorylation of ESR2 and upregulated the AP-1 proteins FOSL2 and JUNB in granulosa cells. Activated MAP kinase ERK2 was associated with the ESR2 phosphorylation in granulosa cells and AP-1 factors could synergistically activate the Kiss1 promoter activity. These gonadotropin-induced changes paralleled Kiss1 expression in granulosa cells. We conclude that gonadotropin-stimulated Kiss1 expression in granulosa cells is dependent upon both the activation of ESR2 and the upregulation of AP-1.////////////////// In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER)-{alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation Emmen JM, et al . Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. Biostatistics Branch, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. Both estrogen receptor alpha and beta (ERalpha and ERbeta) are expressed within the ovary and lack of either of these receptors affects ovarian function. In this study, the role of ERalpha and ERbeta in folliculogenesis and ovulation was further analyzed. Evaluation of ovarian follicle populations in wild-type and ERbeta knockout (betaERKO) ovaries revealed reduced late antral growth and ovulatory capacity of betaERKO follicles, indicated by reduced numbers of large antral follicles and corpora lutea, and increased atresia of large antral follicles. An in vitro culture system was used to study growth, rupture and luteinization of wild-type, ERalpha knockout (alphaERKO) and betaERKO ovarian follicles. alphaERKO follicles exhibited wild-type like growth and ovulation rates but an increased capacity to synthesize estradiol. In contrast, betaERKO follicles showed a significant lack of progression from early antral to large antral stage, decreased estradiol production and reduced ovulation. Expression patterns of several genes involved in follicle maturation and ovulation were analyzed in follicles grown in vitro. Ar, Pgr and Has2 mRNA expression levels were the same among the three genotypes. However, betaERKO follicles showed reduced expression of Cyp19 mRNA during follicle maturation and reduced Lhcgr and Ptgs2 mRNA expression after hCG stimulus. Luteinization occurs normally in alphaERKO and betaERKO follicles, shown by increased progesterone secretion and increased cdkn1b mRNA expression after hCG. Collectively, these data indicate that ERbeta, but not ERalpha, plays a direct role in folliculogenesis. ERbeta appears to facilitate follicle maturation from the early antral to the preovulatory stage. Activin regulates estrogen receptor gene expression in the mouse ovary. Kipp JL et al. Activin, a member of the TGF-beta superfamily, is an important modulator of FSH synthesis and secretion in the pituitary and plays autocrine/paracrine roles in the regulation of ovarian follicle development. From a microarray study on mouse ovarian granulosa cells, we discovered that the estrogen receptor beta (ERbeta) is inducible by activin. We previously demonstrated that estrogen suppresses activin gene expression, suggesting a feedback relationship between these two follicle-regulating hormones. The purpose of this study was to investigate fully activin A regulation of ER expression. Real time RT-PCR assays on cultured granulosa cells showed that both ERalpha and ERbeta mRNAs were induced by activin A at 4, 12 and 24 hrs in a dose-responsive manner. Western blots confirmed an increase in their protein levels. Consistent with increased ERalpha and ERbeta expression, activin A stimulated estradiol-induced estrogen response element (ERE) promoter activity. Activin A stimulation of ER expression was a direct effect at the level of gene transcription, as it was not abolished by cycloheximide but was abolished by actinomycin D, and in transfected granulosa cells activin A stimulated ERalpha promoter activity. To investigate the effect of activin in vivo and thus its biological significance, we examined ER expression in inhibin transgenic mice that have decreased activin expression and discovered that these mice had decreased ERalpha and ERbeta expression in the ovary. We also found that ER mRNA levels were decreased in MIS-Smad 2 dominant negative mice that have impaired activin signaling through Smad 2 and siRNAs targeting Smad 2 or Smad 3 suppressed ERalpha promoter activation, suggesting that Smad 2 and Smad 3 are involved in regulating ER levels. Therefore, this study reveals an important role for activin in inducing the expression of ERs in the mouse ovary and suggests important interplay between activin and estrogen signaling. | ||||
| Ovarian localization | Oocyte, Granulosa, Theca, Luteal cells, Ovarian tumor | ||||
| Comment | Immunohistochemical localization of two estrogen receptor (ER) subtypes, ER beta and ER alpha, was performed in neonatal, early postnatal, immature, and adult rats to determine whether ER alpha and ER beta are differentially expressed in the ovary (Sar et al., 1999). In immature and adult rat ovaries, ER beta was expressed exclusively in nuclei of granulosa cells of primary, secondary, and mature follicles. Atretic follicle granulosa cells showed only weak or no staining. No specific nuclear ER beta IR was detected in thecal cells, luteal cells, interstitial cells, germinal epithelium, or oocytes. In neonatal rat ovary, no ER beta expression was found. In ovaries of 5- and 10-day-old rats, weak ER beta IR was observed in granulosa cells of primary and secondary follicles, but no staining was detected in the primordial follicles. The exclusive presence of ER beta in granulosa cells implies that this specific new subtype of ER beta mediates some effects of estrogen action in the regulation of growth and maturation of ovarian follicles. | ||||
| Follicle stages | Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | Development of Steroid Signaling Pathways during Primordial Follicle Formation in the Human Fetal Ovary. Fowler PA et al. Context: Ovarian primordial follicle formation is critical for subsequent human female fertility. It is likely that steroid, and especially estrogen, signaling is required for this process, but details of the pathways involved are currently lacking. Objective: The aim was to identify and characterize key members of the steroid-signaling pathway expressed in the second trimester human fetal ovary. Design: We conducted an observational study of the female fetus, quantifying and localizing steroid-signaling pathway members. Setting: The study was conducted at the Universities of Aberdeen, Edinburgh, and Glasgow. Patients/Participants: Ovaries were collected from 43 morphologically normal human female fetuses from women undergoing elective termination of second trimester pregnancies. Main Outcome Measures: We measured mRNA transcript levels and immunolocalized key steroidogenic enzymes and steroid receptors, including those encoded by ESR2, AR, and CYP19A1. Results: Levels of mRNA encoding the steroidogenic apparatus and steroid receptors increased across the second trimester. CYP19A1 transcript increased 4.7-fold during this period with intense immunostaining for CYP19A detected in pregranulosa cells around primordial follicles and somatic cells around oocyte nests. ESR2 was localized primarily to germ cells, but androgen receptor was exclusively expressed in somatic cells. CYP17A1 and HSD3B2 were also localized to oocytes, whereas CYP11A1 was detected in oocytes and some pregranulosa cells. Conclusions: The human fetal ovary expresses the machinery to produce and detect multiple steroid signaling pathways, including estrogenic signaling, with the oocyte acting as a key component. This study provides a step-change in our understanding of local dynamics of steroid hormone signaling during the key period of human primordial follicle formation. Using commercial polyclonal antisera against peptides specific to human ER beta, Taylor AH et al determined the sites of ER beta expression in archival and formalin-fixed human tissue and compared its expression with that of ER alpha. In the ovary, ER beta was present in multiple cell types including granulosa cells in small, medium and large follicles, theca and corpora lutea, whereas ER alpha was weakly expressed in the nuclei of granulosa cells, but not in the theca nor in the copora lutea. C?enas et al sequenced the ovine ER?(oER? by using RT-PCR and cloning techniques. The reading frame of oER?contained 527 amino acids and exhibited high overall homology with cow (98%), rat(88%), and human (88%) ER? In addition, an oER?isoform having a 139-base pair deletion (oER?) was identified. Thepredicted amino acid sequence of this isoform is lacking the ligand-binding and carboxyl-terminal transactivation domains.The oER?protein and mRNA were determined in ovaries obtained from ewes on Days 0 (first day of estrus), 2, 6, and 10 of the estrous cycle and Day 30 of gestation. Immunohistochemistry showed that oER?protein was located in granulosa cells, the ovarian surface epithelium, endothelium, and Day 2 corpus luteum (CL). Weak immunostaining for ER?was detected in the theca interna. Relative steady-state amounts of oER?mRNA in the CL were determined using semiquantitative RT-PCR.Amounts of oER?mRNA were greater (P < 0.05) during CL formation (Day 2) than at later stages. The oER?to oER? mRNA ratio was lower (P < 0.05) on Day 2 than on Day 10 or Day 30 due to a decrease in amounts of oER?. | ||||
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9 mutations
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Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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