| inhibin subunit beta A | OKDB#: 1644 |
| Symbols: | INHBA | Species: | human | ||
| Synonyms: | EDF, FRP | Locus: | 7p14.1 in Homo sapiens |
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| General Comment |
Inhibin exists in 2 forms, each of which shares the same alpha subunit and, when covalently linked to 1 of 2 distinct subunits called beta-a and beta-b, inhibits pituitary FSH secretion. On the other hand, the dimers of 2 beta subunits, termed activin, are potent stimulators of FSH secretion and release in vitro.
NCBI Summary: This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate a subunit of the dimeric activin and inhibin protein complexes. These complexes activate and inhibit, respectively, follicle stimulating hormone secretion from the pituitary gland. The encoded protein also plays a role in eye, tooth and testis development. Elevated expression of this gene may be associated with cancer cachexia in human patients. [provided by RefSeq, Aug 2016] |
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| General function | Ligand, Hormone, Growth factor | ||||
| Comment | |||||
| Cellular localization | Secreted | ||||
| Comment | Dynamics of inhibin subunit and follistatin mRNA during development of normal and polycystic ovary syndrome follicles. Fujiwara T et al. (2001) To further explore the developmental dynamics and possible roles of inhibin, activin, and follistatin in the development of human antral follicles as well as the relationship between mRNA and protein levels of these hormones within follicles, quantitative competitive RT-PCR assays were established to determine mRNA levels for the inhibin/activin subunits and both follistatin splice variants. Granulosa cell RNA was obtained by transvaginally aspirating follicles (6-23 mm) from carefully characterized normal women at different times of the follicular phase. alpha- and beta(A)-subunit mRNA levels increased significantly with follicle diameter (r = 0.56; P < 0.01 and r = 0.45; P < 0.05, respectively) and follicle maturity (r = 0.65; P < 0.001 and r = 0.58; P < 0.01, respectively), but beta(B) mRNA levels, which were at least 10-fold lower than levels of the other subunits, showed no relationship to size or maturity. Both follistatin 315 and 288 transcripts were detected in granulosa cells, but neither follistatin transcript varied significantly across the range of follicle sizes analyzed. In addition, granulosa cells contained three follistatin 315 mRNA transcripts for each follistatin 288 transcript, and the follistatin 315/288 ratio did not vary with follicle size. alpha-Subunit mRNA levels were positively associated with dimeric inhibin A protein in human follicular fluid from the same follicle aspirates (r = 0.71; P < 0.001). Similarly, beta(A)-subunit mRNA was associated with inhibin A (r = 0.59; P < 0.01), and beta(B) mRNA was associated with inhibin B (r = 0.67; P < 0.005) in these samples. Thus, the increase in inhibin subunit transcription and protein synthesis with follicle size suggests that inhibin biosynthesis might be important for continued development of the dominant follicle. To explore this hypothesis further, we compared mRNA levels for each of these transcripts in follicles obtained from six polycystic ovary syndrome patients (eight follicles) and compared the results to those from a group (n = 5) of normal follicles matched for mean diameter. Comparisons were also performed for a subset of polycystic ovary syndrome follicles (n = 5) matched for diameter and size range with the normal group. alpha-Subunit mRNA levels were 16-fold lower in both polycystic ovary syndrome follicle groups relative to size-matched normal follicles (P < 0.02), whereas beta(A)-subunit mRNA was significantly lower only when all polycystic ovary syndrome follicles were compared. beta(B)-Subunit and follistatin mRNA levels and the follistatin 315/288 ratio were not statistically different for any group. These results suggest that insufficient production of inhibin alpha and possibly beta(A)-subunits, but not follistatin, is associated with follicular arrest in polycystic ovary syndrome follicles.////////////////// | ||||
| Ovarian function | Follicle endowment, Follicle development, Preantral follicle growth, Antral follicle growth, Cumulus expansion, Steroid metabolism, Germ cell development, Early embryo development | ||||
| Comment | Activin effects on follicular growth in in vitro preantral follicle culture. Tanaka Y et al. (2019) As the follicular environment transits from being activin dominant to inhibin dominant during folliculogenesis, it is assumed that activin plays an important role in the early stage of follicular growth. We examined the effects of activin on morphological, biochemical and molecular changes in isolated preantral follicles. Preantral follicles were mechanically isolated from 14-day old female C57BL/6 mice. Each follicle was cultured and observed for 14 days usingan in vitro follicle culture system containing FSH, FSH + activin A and FSH + inhibin in the culture medium. We subsequently examined FSH receptor (FSH-R) mRNA expression in isolated follicle cultures with or without activin on days 0 and 2. Activin was observed to significantly stimulate follicle enlargement on days 2, 4, 6 and 8, accelerate morphological changes and increase estradiollevels in culture medium on days 4, 12 and 14. In contrast, inhibin did not alter follicular growth. Additionally, activin stimulated the expression of FSH-R mRNA in isolated granulosa cells. It was demonstrated that activin stimulated the growth of preantral follicles, mainly during the early stage of folliculogenesis, by inducing FSH-R expression, in an isolated follicle culture system. J. Med. Invest. 66 : 165-171, February, 2019.//////////////////Effects of activin A on the transcriptome of mouse oogenesis in vitro. Wang JJ et al. (2019) From the previous research, it has been supported that activin A (ActA) is conducive to ovarian development in vitro. In the present paper, with the aim to identify the molecular pathways through which ActA can influence processes of the fetal and early postnatal oogenesis, we analyzed the transcriptome of embryonic ovaries (12.5 days postcoitum) in vitro cultured with or without ActA for 6 days, as well as the produced oocytes for 28 days, and further compared the gene expression profile with their in vivo counterparts. With the confirmation of designed test, we found that the addition of ActA to the ovary culture tended, generally, to align oocyte gene expression to the in vivo condition, in particular of a number of genes involved in meiosis and epigenetic modifications of histones. In particular, we identified DNA recombination during the oocyte meiotic prophase I and lysine trimethylation of the histone H3K27 during the oocyte growth phase as molecular pathways modulated by ActA.////////////////// Activin A and follistatin during the oestrous cycle and early pregnancy in ewes. O'Connell AR et al. (2016) The activin pathway has been postulated to be involved in regulation of multiple reproductive processes important for survival of the conceptus. These processes include luteinisation of the follicular cells and thus function of the corpus luteum, early embryo development, and uterine function including implantation of the conceptus. Therefore, the aim of the current study was to determine whether the concentrations of activin A and follistatin (FST), an activin binding protein, differed between ewes with a lifetime history of enhanced or reduced embryonic survival. The mRNAs encoding FST and activin A (inhibin beta A subunit, INHBA) were present in the uterus and abundant in the uterine luminal or glandular epithelia by day 18 of gestation. A peak of activin A was observed in the systemic circulation around the time of oestrus and activin A concentrations were elevated in animals with reduced embryonic survival during the oestrous cycle and early gestation. Concentrations of activin A in uterine fluid were approximately two-fold greater on day 16 of gestation in ewes with reduced embryonic survival compared to those with enhanced embryonic survival. No consistent differences in FST were observed between these groups. Treatment of luteinising ovine granulosa cells with activin A in vitro suppressed progesterone secretion providing evidence of a potential pathway whereby increased concentrations of activin A may decrease embryonic survival.////////////////// Effects of Recombinant Activins on Steroidogenesis in Human Granulosa-Lutein Cells. Chang HM 2014 et al. Context: Exerting a broad range of biological effects in various tissues, activins are homo- or heterodimers of activin/inhibin subunits (A, B, C and E in humans). While activins A (AA), B (BB), AB (AB) and AC (AC) have been demonstrated in the female reproductive system, little is known about their individual functions in the ovary. Objective: To investigate the biological roles and activities of activins in regulating steroidogenesis in human granulosa cells. Design: Human granulosa-lutein cells obtained from 32 patients undergoing in vitro fertilization were used to investigate the effects of activin A, B, AB and AC on the expression of steroidogenic enzymes and steroid production. Setting: An academic research center. Main Outcome Measures: mRNA and protein levels were examined by RT-qPCR and Western blot analysis, respectively. The production of estradiol and progesterone were measured by enzyme immunoassay. Results: P450 aromatase, FSH receptor and estradiol levels were increased, whereas StAR, LH receptor and progesterone levels were decreased, following treatment with activin A, B and AB, but not activin AC. FSH or LH induced the production of aromatase/estradiol and StAR/progesterone; however pre-treatment with activin A, B or AB enhanced the effects of gonadotropins on aromatase/estradiol, but suppressed their effects on StAR/progesterone. Treatment with activin A, B or AB induced the phosphorylation of SMAD2 and 3, whereas activin AC had no such effects. Furthermore, co-culture of activin AC (1-100 ng/ml) with activin A (25 ng/ml) did not alter the effects of activin A on P450 aromatase or StAR mRNA levels. Conclusion: Activin A, B and AB have similar effects on steroidogenesis in human granulosa cells. In contrast, activin AC is not biologically active and does not act as a competitive antagonist. ///////////////////////// Recombinant activin a enhances the growth and survival of isolated preantral follicles cultured three-dimensionally in extracellular basement matrix protein (matrigel) under serum-free conditions. Guzel Y 2014 et al. Abstract Development of in vitro technologies that will allow the culture of early stage follicles before antral stage is an essential part of research in reproductive biology in order to understand the ovarian folliculogenesis better. Current evidence suggests that oocyte and somatic cells-derived growth factors interacting with each other and extracellular matrix proteins at paracrine level are involved in this early, gonadotrophin-independent phase of follicle growth. Basement membrane matrix protein (Matrigel?) is a soluble gel rich in extracellular matrix proteins and growth factors. Activin A promotes preantral follicle growth in vivo by inducing the proliferation of granulosa cells and by upregulating the expression of FSH receptor and aromatase enzyme. We hypothesized that activin A and matrigel may provide a better in vitro environment for early stage preantral follicles. Preantral follicles isolated from 14-21 day old BALB/c mice were cultured in matrigel???activin A for four days. The growth (119.4% versus 45.4%, p?Hammami S 2013 et al. The present study was designed to evaluate the effect of activin-A during the in vitro oocyte maturation (IVM) and in vitro embryo culture (IVC) on nuclear maturation, blastocyst yield and blastocyst quality of prepubertal goat oocytes. In Experiment 1, three groups of oocytes were used during the IVM of prepubertal goat oocytes to determine the optimal concentration of recombinant human activin-A added to the maturation medium. Cumulus-oocyte complexes were matured in an IVM medium containing 0, 10 and 100 ng/ml (groups A0, A10 and A100), fertilized and in vitro cultured using standard procedures. In Experiment 2, the addition of 10 ng/ml activin-A at IVM (A10A0), IVC (A0A10) or IVM+IVC (A10A10) was studied and compared with the control group (A0A0). Results of the first experiment demonstrated that the addition of activin-A yielded similar percentages of maturation (?71.0%) and blastocyst formation rates (?24.9%) than the control group (A0). Experiment 2 showed that exposure of prepubertal goat oocytes to an IVC medium containing 10 ng/ml activin-A (A0A10) significantly increased the rates of development to the blastocyst stage, as compared with the control group (A0A0) (19.5?2.21% v. 13.1?2.37%, respectively; P<0.05). With regard to the blastocyst quality, total number of cells, inner cell mass (ICM) and trophectoderm of prepubertal goat embryos produced in the presence of activin-A did not differ significantly among experimental groups. In summary, these results indicate that supplementation of the IVC medium with activin-A enhances embryo development of prepubertal goat oocytes. ///////////////////////// Activin-A promotes the development of goat isolated secondary follicles in vitro. da Silva CM 2013 et al. Summary The role of activin-A in follicular development and on the mRNA expression levels of different genes in goat secondary follicles was evaluated. Goat secondary follicles (=150 ?m) were cultured for 18 days under control conditions or with the addition of either 50 or 100 ng/ml activin-A (Experiment 1). The mRNA levels for the genes that code for activin-A, ActR-IA, ActR-IB, ActR-IIA, ActR-IIB, follicle stimulating hormone receptor (FSH-R) and P450 aromatase were measured in each condition (Experiment 2). We observed that after 6 days of culture, the antrum formation rate was higher in cultures with added activin-A than in the cultured control (P < 0.05). The addition of 50 ng/ml activin-A increased the follicular growth rate in the final third of the culture (days 12-18), resulting in a higher percentage of meiosis resumption (P < 0.05). On day 6, the addition of activin-A (50 ng/ml) increased the levels of ActR-IA mRNA compared with the cultured control (P < 0.05). After 18 days, the addition of 50 ng/ml activin-A significantly increased the levels of its own mRNA compared with the non-cultured control. Moreover, this treatment reduced the mRNA levels of P450 aromatase in comparison with the cultured control (P < 0.05). Higher levels of P450 aromatase mRNA were found for both activin-A treatments compared with the non-cultured control (P < 0.05). No difference in estradiol levels was detected among any of the tested treatments. In conclusion, the addition of activin-A to culture medium stimulated early antrum formation as well as an increase in the daily follicular growth rate and the percentage of meiosis resumption. ///////////////////////// Activin promotes ovarian follicle development in vitro. Li R et al. Activin is a protein originally isolated from follicular fluid as a factor stimulating FSH release from the pituitary. The present experiments support the hypothesis that activins may also regulate follicle development by autocrine/paracrine mechanisms. Granulosa-oocyte complexes were isolated by collagenase/dispase dispersion of ovaries from 14- or 21-day-old rats and cultured in serum-free medium. Within 24 h, the cells had spread to form a monolayer. Hormones and growth factors were added at this time. Cell number and thymidine incorporation were measured after an additional 72 h. In the presence of insulin and transferrin, activin-A increased both granulosa cell number and thymidine incorporation more than 2-fold. This effect could be inhibited by follistatin, an activin-binding protein. In addition, activin-A, in the presence of FSH, induced reorganization of follicular structures from monolayer culture of cells from 14-day-old rats and caused cells from primary follicles to develop into large follicle-like structures. These structures contained oocytes, a cumulus layer, an antrum, and a multilayered follicular wall with a diameter of more than 1 mm. Electron microscopy revealed that the cells in the follicle-like structure were connected by gap junctions. Oocytes showed a mature morphology and had closely associated cumulus layers. Dissociation of the follicular wall in these follicle-like structures was induced by the addition of LH, resembling the induction of ovulation in vivo. The findings are important for understanding follicular development and atresia. A comparative study on transforming growth factor-beta and activin A for preantral follicles from adult, immature, and diethylstilbestrol-primed immature mice. Liu X et al. Both transformation growth factor-beta (TGFbeta) and activin belong to the TGFbeta superfamily, and each receptor is structurally related. We have shown that the action of activin A on folliculogenesis is different in immature and adult mice, so it is of interest to study whether TGFbeta has such an action on follicular development. The effect of TGFbeta on folliculogenesis was studied in isolated preantral follicles from immature, adult, and diethylstilbestrol (DES)-primed immature mice and was compared with that of activin A. TGFbeta caused a significant increase in follicular diameter and estradiol and immunoreactive inhibin secretion in adult mice in a dose-related manner, but did not affect the size of preantral follicles from immature mice. Activin A, on the other hand, caused a significant increase in the size of follicles from immature mice, but did not change the size of preantral follicles from adult mice. TGFbeta enhanced the effect of FSH, whereas activin A completely blocked the action of FSH on preantral follicles from adult mice. Such a specific action of TGFbeta and activin A was age dependent because preantral follicles obtained from 28-day-old mice, compared with those from 11- and 56-day-old mice, showed an intermediate reaction to TGFbeta and activin A. DES pretreatment of 11- and 28-day-old mice caused an enhanced response to FSH, but this response was completely inhibited by TGFbeta. These results indicate that both TGFbeta and activin A have proliferative action and cytodifferentiative action on granulosa cells, but the action of each is age dependent and opposite in direction. In conclusion, although both TGFbeta and activin A belong to the same family, and each receptor is structurally related, both share a specific role in early folliculogenesis before and after puberty. Activin from secondary follicles causes small preantral follicles to remain dormant at the resting stage. Mizunuma H et al. The purpose of the present study was to investigate 1) whether activin A can cause primary follicles to become dormant at the resting stage, and 2) the role of the secondary follicle on follicular growth of primary follicles. Preantral follicles (100-120 microm in diameter) harvested from adult mice and cultured in in vitro follicle culture system showed a significant increase in size and estrogen and inhibin secretion in response to FSH, but the administration of activin A blocked the effect of FSH. Withdrawal of activin A not only restored the follicular response to FSH but also enhanced the effect of FSH, indicating that the action of activin A is to cause small preantral follicles to become dormant at the preantral stage. To investigate the role of secondary follicles in early folliculogenesis, small preantral follicles were cocultured with secondary follicle (300-350 microm in diameter) in the presence of FSH. The secondary follicle showed a significant increase in follicular diameter as a result of stimulation by FSH, but the small preantral follicles did not increase in size. After removal of the secondary follicle, however, the small preantral follicles commenced follicular growth, indicating that the growth of small preantral follicles is suppressed by the secondary follicle. Administration of the activin binding protein follistatin caused a significant increase in follicular diameter of both small preantral and secondary follicles as a result of stimulation by FSH. These results have suggested that secondary follicles cause primary follicles to become dormant at the resting stage by secreting activin. Activin Promotes Follicular Integrity and Oogenesis in Cultured Preantral Bovine Follicles. McLaughlin M et al. The aim of this study was to determine the individual and combined effect of activin and FSH on somatic and germ cell development in cultured preantral follicles. Preantral bovine follicles (mean diameter 157+/-3, range 132-199 microm) were cultured for 8 days in serum-free medium in the presence of either 100ng/ml of recombinant human activin A (rhAct A), 100ng/ml rhAct A combined with a high (100ng/ml) or low (50ng/ml) concentration of recombinant FSH (rFSH) or 50ng/ml rFSH alone. Intrafollicular connexin 43 expression and actin-based cell adhesion were assessed on Day 2 and 4 of culture. Steroidogenesis was evaluated after Day 4 and 8. Follicles exposed to 100ng/ml activin maintained expression of connexin 43 at the follicular periphery. In the presence of activin, with or without 100ng/ml or 50ng/ml FSH, follicles were steroidogenic undergoing significant growth (p<0.01), granulosa cell proliferation (p<0.01) and antral cavity formation (p<0.05) compared to cultured controls. Maximum oocyte growth occurred in the presence of 100ng/ml activin alone with a significant percentage of these oocytes maintaining normal morphology over controls (p<0.05). These results are consistent with a role for activin in maintaining oocyte granulosa cell interactions due to increased peripheral granulosa cell adhesion to the basement membrane and retention of adhesion at the surface of the zona pellucida. Thus, the polarised expression of cell contact interactions promoted by activin supports ongoing folliculogenesis. Inhibins are one of the most important protein hormone secreted by the ovary and responsible for both endocrine feedback regulation of the pituitary FSH release and paracrine regulation of local ovarian functions.The literature on inibibin and ovarian function has been summarized by Mather et al. (1997) , Woodruff et al. (1995) and Hillier et al. (1993). Hsueh et al. (1987) tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In cultured ovarian theca-interstitial cells and theca explants, the alpha beta heterodimer of inhibin enhances androgen biosynthesis stimulated by LH, whereas the activin beta beta homodimer suppresses androgen production. These data indicate that the inhibin-related gene products synthesized by granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis. Modulatory actions of activin-A and follistatin on the developmental competence of in vitro-matured bovine oocytes. Silva CC et al. The presence of activin receptors on oocytes and granulosa cells suggests that activin and its binding protein, follistatin, may regulate oocyte maturation. The aim of the present study was to investigate whether activin-A and follistatin can influence the in vitro maturation of bovine oocytes as assessed by their competence to form blastocysts after in vitro fertilization. Bovine cumulus oocyte complexes (COCs) were cultured for 22-24 h at 38.5 degrees C in tissue culture medium-199 supplemented with 10% estrous cow serum, eCG (2.5 IU/ml), and either no treatment (control), activin-A (0.1 or 0.5 microg/ml), follistatin (0.1, 1, or 10 microg/ml), or activin-A (0.5 microg/ml) in combination with follistatin (0.5 or 5 microg/ml). In separate experiments, the same treatments were also tested on cumulus-free oocytes, which had a much reduced developmental capacity when compared to COCs. Neither activin-A nor follistatin affected the postfertilization cleavage rate of either COCs (approximately 60%) or cumulus-free oocytes (approximately 40%). Activin increased (p < 0.05) the proportion of cleaved oocytes that reached the blastocyst stage when added to both COCs (38% increase) and cumulus-free oocytes (160% increase), with the magnitude of response much greater with the latter. Follistatin had a dose-dependent inhibitory effect on blastocyst yield from COCs (67% reduction, p < 0.05) and opposed the stimulatory effect of activin (p < 0.05). With cumulus-free oocytes, however, follistatin did not further decrease the low developmental potential of oocytes. A positive correlation (r = 0.57, p < 0.001) was found between endogenous levels of activin-A produced by COCs and their postcleavage development to the blastocyst stage. No such correlation was found between endogenous follistatin level and postcleavage development (r = 0.10, p = 0.46). Endogenous levels of activin-A and follistatin secreted by cumulus-free oocytes were undetectable. These in vitro observations support the hypothesis that activin-A and follistatin, both secretory products of cumulus cells, contribute to the regulation of oocyte maturation in vivo. Postnatal regulation of germ cells by activin: The establishment of the initial follicle pool. Bristol-Gould SK et al. Mammalian females enter puberty with follicular reserves that exceed the number needed for ovulation during a single lifetime. Follicular depletion occurs throughout reproductive life and ends in menopause, or reproductive aging, when the follicle pool is exhausted. The mechanisms regulating the production of a species-specific initial follicle pool are not well understood. However, the establishment of a follicular reserve is critical to defining the length of reproductive cyclicity. Here we show that activin A (rh-ActA), a known regulator of follicle formation and growth in vitro, increased the number of postnatal mouse primordial follicles by 30% when administered to neonatal animals during the time of germline cyst breakdown and follicle assembly. This expansion in the initial follicle pool was characterized by a significant increase in both germ cell and granulosa cell proliferation. However, the excess follicles formed shortly after birth did not persist into puberty and both adult rh-ActA- and vehicle-treated animals demonstrated normal fertility. A follicle atresia kinetic constant (k(A)) was modeled for the two groups of animals, and consistent with the empirical data, the k(A) for rh-ActA-treated was twice that of vehicle-treated animals. Kinetic constants for follicle formation, follicle loss and follicle expansion from birth to postnatal day 19 were also derived for vehicle and rh-ActA treatment conditions. Importantly, introduction of exogenous rh-ActA revealed an intrinsic ovarian quorum sensing mechanism that controls the number of follicles available at puberty. We propose that there is an optimal number of oocytes present at puberty, and when the follicle number is exceeded, it occurs at the expense of oocyte quality. The proposed mechanism provides a means by which the ovary eliminates excess follicles containing oocytes of poor quality prior to puberty, thus maintaining fertility in the face of abnormal hormonal stimuli in the prepubertal period. Oocyte-Secreted Factor Activation of SMAD 2/3 Signaling Enables Initiation of Mouse Cumulus Cell Expansion. Dragovic RA et al. Expansion of the mouse cumulus-oocyte complex (COC) is dependent on oocyte-secreted paracrine factors. TGFB superfamily molecules are prime candidates for the cumulus expansion-enabling factors (CEEFs), and we have recently determined that growth differentiation factor 9 (GDF9) alone is not the CEEF. The aim of this study was to examine oocyte paracrine factors and their signaling pathways that regulate mouse cumulus expansion. Using RT-PCR oocytes were found to express the two activin subunits, Inhba and Inhba, and activin A and activin B both enabled FSH-induced cumulus expansion of oocytectomized (OOX) complexes. Follistatin, an activin binding protein, neutralized activin-induced expansion, but had no effect on oocyte-induced expansion. The type-I receptors for GDF9 and activin are activin receptor-like kinase 5 (ALK5) and ALK4, respectively, both of which activate the same SMAD 2/3 signaling pathway. We examined the requirement for this signaling system using an ALK4/5/7 inhibitor, SB-431542. SB-431542 completely ablated FSH-stimulated GDF9-, activin A-, activin B- and oocyte-induced cumulus expansion. Moreover, SB-431542 also antagonized EGF-stimulated oocyte-induced cumulus expansion. Using real-time RT-PCR, SB-431542 also attenuated GDF9-, activin A- and oocyte-induced OOX expression of hyaluronan synthase-2, tumour necrosis factor alpha-induced protein-6, prostaglandin synthase-2 and pentraxin-3. This study provides evidence that the CEEF is composed of TGFB superfamily molecules that signal through SMAD 2/3 to enable the initiation of mouse cumulus expansion. Activin signals via SMAD2/3 between germ and somatic cells in the human fetal ovary and regulates kit ligand expression. Coutts SM et al. Ovarian germ cell survival is dependent upon the formation of primordial follicles, which occurs during fetal life in the human. Activin contributes to germ cell proliferation and survival at this time. SMADs2 and 3 are central elements in the activin signalling pathway and thus indicate sites of activin action. We have investigated the expression and localisation of SMADs2 and 3 in the fetal ovary between 14 and 20 weeks gestation, i.e. preceding and during primordial follicle formation. SMAD3 mRNA expression increased 1.9 fold (P=0.02). SMAD2 and 3 proteins were localised by immunofluorescence to the nuclei of three distinct populations of somatic cells: (a) stromal cells between clusters of germ cells; (b) some somatic cells intermingled with activin betaA-expressing germ cells; (c) pre-granulosa cells surrounding primordial follicles. Germ cells did not express SMAD2 or 3. Activin A increased and follistatin decreased phosphorylation of SMAD2/3 in vitro, and activin increased SMAD2 and decreased KITLG mRNA expression. It therefore appears that somatic cells are the targets for activin signalling in the developing ovary. The effects of activin on germ cells are indirect and include mediation by the kit ligand/c-Kit pathway, rather than being an autocrine germ cell effect. | ||||
| Expression regulated by | Steroids, mir34a | ||||
| Comment | miR-34a targets the inhibin beta B gene, promoting granulosa cell apoptosis in the porcine ovary. Tu F 2014 et al. During ovarian follicular growth and development, only a few follicles actually ovulate. Recently, it was found that follicular atresia is triggered by granulosa cell apoptosis, but the molecular mechanism of follicular atresia was not understood. Using flow cytometry, we found that miR-34a promotes granulosa cell apoptosis in pig ovarian follicles. In addition, inhibin beta B was found to be a miR-34a target gene, based on luciferase reporter assays, quantitative RT-PCR and Western blotting. Taken together, our data indicate that miR-34a plays an important role in granulosa cell apoptosis by targeting the INHBB gene in the porcine ovary. ///////////////////////// Exposure to Estrogens Suppresses Activin Expression and Signaling in the Mouse Ovary. Kipp JL et al. In the ovary, the steroid hormone estrogen and the TGF-beta superfamily member activin are both produced by granulosa cells and they both have intra-ovarian functions. Emerging evidence has indicated an interaction of these two signaling pathways. Based on the fact that estrogen and activin can impact early follicle formation and development, we hypothesize that estrogen treatment may alter activin signaling in the neonatal ovary. Therefore, this study was designed to examine the effect of neonatal DES and E2 exposure on the mRNA and protein levels of the key factors involved in activin signaling in the mouse ovary. CD-1 mouse pups were given daily injections of diethylstilbestrol (DES), estradiol (E2) or oil on postnatal days 1-5, and ovaries and sera were collected on day 19. Neonatal DES or E2 exposure decreased the number of small antral follicles, induced multi-oocytic follicle (MOF) formation, and decreased activin beta subunit mRNA and protein levels. Consistent with local loss of beta subunit expression, the phosphorylation of Smad 2, a marker of activin-dependent signaling, was decreased in the estrogen-treated ovaries. The decreased beta subunit expression resulted in a decrease in serum inhibin levels, with a corresponding increase in FSH. Estrogen also suppressed activin subunit gene promoter activities, suggesting a direct transcriptional effect. Overall, this study demonstrates that activin subunits are targets of estrogen action in the early mouse ovary. | ||||
| Ovarian localization | Primordial Germ Cell, Cumulus, Granulosa | ||||
| Comment | Findlay JK, et al reviewed studies on the production and actions of inhibin and activin during folliculogenesis in the rat. Evidence to enhance the premise that inhibin and activin are local regulators of ovarian folliculogenesis is presented in this review. Granulosa cells (GC) have been identified as the source of inhibin/activin in the ovary on the basis of mRNA and protein localisation and the measurement of the inhibin forms in GC conditioned media. Expression of the subunit mRNAs changed with follicular development, being maximal in the ovaries of 8-day-old rats, where secondary follicles predominate. The expression of beta subunit mRNAs by GC isolated from diethylstilboestrol (DES)-treated immature rats, was reduced in the absence of any change in alpha subunit mRNA expression. Dimeric inhibin-A, -B and free alpha subunit were produced by ovarian cell cultures prepared from 4- to 12-day-old rats. Inhibin-A production by these cultures was responsive to FSH and TGF-beta, with preantral follicles of day 8 ovaries exerting effects so profound that the inhibin A/alpha subunit ratio increased, most likely due to a stimulation of beta(A) subunit production. In contrast, inhibin-B was not stimulated by TGF-beta until day 8 and FSH until day 12. Fractionation of GC conditioned media revealed a prominence of free alpha subunit and inhibin-A, but little inhibin-B, suggesting that inhibin-B production declines with follicular development. Activin receptor types I and II, Smads 1-8 and betaglycan (beta-glycan) mRNAs were present in the rat ovary and showed distinct patterns of expression between postnatal days 4 and 12. Oocytes and GC localised activin receptor, Smad and beta-glycan proteins, with beta-glycan also present in theca cells (TC). These data indicate that activin/TGF-beta signalling machinery and factors which influence these pathways, are present in the postnatal rat ovary. Inhibin and activin play important and changing autocrine/paracrine roles in the growth and differentiation of follicles, including the oocyte, has been supported by these studies.da Silva SJ, et al reported the expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation. The formation of the essential functional unit of the ovary, the primordial follicle, occurs during fetal life in humans. Factors regulating oogonial proliferation and interaction with somatic cells before primordial follicle formation are largely unknown. We have investigated the expression, localisation and functional effects of activin and its receptors in the human fetal ovary at 14-21 weeks gestation. Expression of mRNA for the activin betaA and betaB subunits and the activin receptors ActRIIA and ActRIIB was demonstrated by RT-PCR. Expression of betaA mRNA increased 2-fold across the gestational range examined. Activin subunits and receptors were localised by immunohistochemistry. The betaA subunit was expressed by oogonia, and the betaB subunit and activin receptors were expressed by both oogonia and somatic cells. betaA expression was increased in larger oogonia at later gestations, but was low in oocytes within newly formed primordial follicles. Treatment of ovary fragments with activin A in vitro increased both the number of oogonia present and oogonial proliferation, as detected by bromodeoxyuridine (BrdU) incorporation. These data indicate that activin may be involved in the autocrine and paracrine regulation of germ cell proliferation in the human ovary during the crucial period of development leading up to primordial follicle formation. | ||||
| Follicle stages | Primary, Secondary, Antral, Preovulatory | ||||
| Comment | Follicle Size Class Contributes to Distinct Secretion Patterns of Inhibin Isoforms During the Rat Estrous Cycle Kenny HA, et al . The differential production of inhibins must be exquisitely controlled at the cellular level to ensure the secretion of the appropriate ligand at specific times during the reproductive cycle. The mechanisms underlying inhibin dimer assembly, processing and secretion are not well understood. Here we verify that the secretion of inhibin A and inhibin B from the granulosa cell is discordant during the estrous cycle: Discordant production or secretion of the inhibins was not observed during the PMSG induced cycle. We correlated the discordant production and secretion of inhibin A and inhibin B into the serum with distinct patterns of inhibin alpha- and beta- subunit colocalization during the cycle in granulosa cells. We determined that the discordant pattern of inhibin A and inhibin B during the rat estrous cycle is due to independent populations of antral follicles making inhibin B (small antral follicles) or inhibin A (large antral follicles). | ||||
| Phenotypes | |||||
| Mutations |
5 mutations
Species: mouse
Species: mouse
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Nov. 6, 2002, 2:09 p.m. | by: |
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| last update: | Aug. 14, 2020, 1:42 p.m. | by: | hsueh email: |
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