| follistatin | OKDB#: 190 |
| Symbols: | FST | Species: | human | ||
| Synonyms: | FS | Locus: | 5q11.2 in Homo sapiens |
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| General Comment |
Ueno et al. (1987) isolated a Mr 35,000 protein with follicle-stimulating hormone release-inhibitory activity from porcine ovarian follicular fluid by heparin-Sepharose affinity chromatography, gel filtration on Sephacryl S-200, and multiple steps of high-performance liquid chromatography. The isolated molecule is highly enriched in cysteines and is composed of a single polypeptide chain. This protein specifically inhibits the basal secretion of follicle-stimulating hormone, but not that of luteinizing hormone, in the rat anterior pituitary monolayer culture system. Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes Beverdam A, et al. Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes Beverdam A, et al.
PMID: 1909791
NCBI Summary: Follistatin is a single-chain gonadal protein that specifically inhibits follicle-stimulating hormone release. The single FST gene encodes two isoforms, FST317 and FST344 containing 317 and 344 amino acids respectively, resulting from alternative splicing of the precursor mRNA. In a study in which 37 candidate genes were tested for linkage and association with polycystic ovary syndrome (PCOS) or hyperandrogenemia in 150 families, evidence was found for linkage between PCOS and follistatin. [provided by RefSeq, Jul 2008] |
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| General function | Extracellular binding protein | ||||
| Comment | Follistatin is an activin-binding protein that can act as an activin antagonist in vitro (Nakamura et al. 1990). Follistatin also binds heparin sulfate proteoglycans and may function as a reservoir for activins in vivo. Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatinGlister C, et al . Given the paucity of information on the potential roles of bone morphogenetic proteins (BMPs) in the ruminant ovary we conducted immunolocalization and functional studies on cells isolated from bovine antral follicles. Immunocytochemistry revealed expression of BMP-4 and -7 in isolated theca cells whereas granulosa cells and oocytes selectively expressed BMP-6. All three cell types expressed a range of BMP-responsive type-I (BMPRIB, ActRI) and type-II (BMPRII, ActRII, ActRIIB) receptors supporting autocrine/paracrine roles within the follicle. This was reinforced by functional experiments on granulosa cells which showed that BMP-4, -6 and -7 promoted cellular accumulation of phosphorylated Smad-1 but not Smad-2 and enhanced 'basal' and IGF-stimulated secretion of oestradiol (E2), inhibin-A, activin-A and follistatin (FS). Concomitantly, each BMP suppressed 'basal' and IGF-stimulated progesterone secretion, consistent with an action to prevent or delay atresia and/or luteinization. BMPs also increased viable cell number under 'basal' (BMP-4 and -7) and IGF-stimulated (BMP-4, -6 and -7) conditions. Since FS, a product of bovine granulosa cells, has been shown to bind several BMPs, we used the Biacore technique to compare its binding affinities for activin-A (prototype FS ligand) and BMP-4, -6 and -7. Compared with activin-A (K(d) 0.28 +/- 0.02 nM; 100%), the relative affinities of FS for BMP-4, -6 and -7 were 10, 5 and 1% respectively. Moreover, studies on granulosa cells showed that preincubation of ligand with excess FS abolished activin-A-induced phosphorylation of Smad-2 and BMP-4-induced phosphorylation of Smad-1. However, FS only partially reversed BMP-6-induced Smad-1 phosphorylation and had no inhibitory effect on BMP-7-induced Smad-1 phosphorylation. These findings support functional roles for BMP-4, -6 and -7 as paracrine/autocrine modulators of granulosa cell steroidogenesis, peptide secretion and proliferation in bovine antral follicles. The finding that FS can differentially modulate BMP-induced receptor activation and that this correlates with the relative binding affinity of FS for each BMP type implicates FS as a potential modulator of BMP action in the ovary. | ||||
| Cellular localization | Secreted | ||||
| Comment | Mather et al. (1997) reviewed studies on activins, inhibins, and follistatins. Sugino et al reported that follistatin (FS) is a monomer derived from two polypeptide core sequences of 315 (FS-315) and 288 (FS-288) amino acids originated from alternatively spliced mRNA. They purified six molecular forms of FS from porcine ovaries. Protein chemical analysis revealed that the structural differences among the six isoforms were caused by truncation of the carboxyl-terminal region and/or the presence of carbohydrate chains, resulting in the formation of FS-315, FS-288, and FS composed of 303 amino acids (FS-303) in various forms of glycosylation on the two potential Asn-linked glycosylation sites. The majority of FS isolated from porcine ovaries was FS-303, which may have been derived from FS-315 by proteolytic cleavage of the 12 COOH-terminal amino acids. All six molecular species have almost the same activin binding activity. They suggest that cell-associated FS traps activin more tightly in the matrix, thereby more effectively blocking the activity of activin on heparan sulfate proteoglycans of the cell surface and that cell-associated FS plays an important role in controlling the various actions of activin in a paracrine or autocrine manner. Evans et al described an ultra-sensitive two-site enzyme immunoassay using a pair of mouse monoclonal antibodies raised against follistatin 288. The presence of sodium deoxycholate and Tween 20 in the diluent gave results for total (free and activin-dissociated) follistatin. Pooled human follicular fluid contained high concentrations of follistatin (approximately 242 ng/ml). Follistatin was also found in maternal serum during pregnancy, amniotic fluid, seminal plasma and human granulosa cell conditioned media (approximately 0.44 ng/ml). Serial serum samples taken throughout the menstrual cycle of ten women showed fluctuating follistatin concentrations (approximately 0.62 ng/ml) with no apparent relationship to the stage of the cycle. Pooled serum from postmenopausal women appeared to have higher follistatin levels than any of the normal women (approximately 1.4 ng/ml). Wang et al reported the assembly of a series of FS-activin/inhibin complexes in a variety of organ systems that may impact upon the available amount of free versus bound (or "complexed") ligand, which must be considered when investigating the biology of activin- or inhibin-responsive cells. In addition, urine may be an important biological fluid that can be used to measure significant changes in circulating FS complexes. | ||||
| Ovarian function | Follicle endowment, Follicle development, Steroid metabolism, Luteinization, Early embryo development | ||||
| Comment | Follistatin288 Regulates Germ Cell Cyst Breakdown and Primordial Follicle Assembly in the Mouse Ovary. Wang Z et al. (2015) In mammals, the primordial follicle pool represents the entire reproductive potential of a female. The transforming growth factor-β (TGF-β) family member activin (ACT) contributes to folliculogenesis, although the exact mechanism is not known. The role of FST288, the strongest ACT-neutralizing isoform of follistatin (FST), during cyst breakdown and primordial follicle formation in the fetal mice ovary was assessed using an in vitro culture system. FST was continuously expressed in the oocytes as well as the cuboidal granulosa cells of growing follicles in perinatal mouse ovaries. Treatment with FST288 delayed germ cell nest breakdown, particularly near the periphery of the ovary, and dramatically decreased the percentage of primordial follicles. In addition, there was a dramatic decrease in proliferation of granulosa cells and somatic cell expression of Notch signaling was impaired. In conclusion, FST288 impacts germ cell nest breakdown and primordial follicle assembly by inhibiting somatic cell proliferation.////////////////// Disruption of follistatin by RNAi increases apoptosis, arrests S-phase of cell cycle and decreases estradiol production in bovine granulosa cells. Chong Z et al. (2015) Follistatin (FST), a local regulator of gonadal functions is a powerful inhibitor of follicle stimulating hormone (FSH) secretion. In the present study, the expression of FST was partially silenced at both transcriptional and translational levels by RNAi-Ready pSIREN-RetroQ-ZsGreen Vector mediated recombinant pshRNA vectors in bovine granulosa cells (bGCs). The results showed that transfection with FST-1 and FST-2 vectors significantly down-regulated mRNA and protein expressions of follistatin by 51% (P=0.0093) and 72% (P=0.0078) respectively. After down-regulation of FST in bGCs, cell cycle was arrested at S-phase (9.2±0.6 vs 12.5±0.2, P=0.0055), and apoptosis was significantly (21.3±2.7 vs 13.9±2.5, P=0.0051) increased. These findings were further verified by down-regulation of protein level of B-cell leukemia/lymphoma 2 (Bcl2, P=0.0423), and up-regulation of caspase-3 (P=0.0362), p21 (P=0.0067) and mRNA levels of Bcl2-associated X protein (Bax, P=0.041). Knockdown of FST in bGCs significantly increased activin A concentration in culture medium, while level of estradiol (E2) was suppressed without affecting progesterone production. In addition, mRNA levels of all activin receptor subtypes activin receptor types I (ACRI) and II (ACRIIA and ACRIIB)] and inhibin α-subunit were augmented (P<0.05) without altering both inhibin β-subunits. These findings suggest that follistatin may participate in caspase3-dependent apoptosis through Bcl2/Bax gene family in bovine GCs, whereas, activin and its receptors are associated with its regulation. Activin-induced up-regulation of inhibin-α subunit in bGCs seems to be involved in the regulation of steroidogenesis.////////////////// Differential Effects of Follistatin on Nonhuman Primate Oocyte Maturation and Pre-Implantation Embryo Development In Vitro. [Vandevoort CA et al. There is a vital need to identify factors that enhance human and nonhuman primate in vitro embryo culture and outcome and identify the factors that facilitate that objective. Granulosa and cumulus cells were obtained from rhesus monkeys that had either been FSH-primed (in vitro maturation - IVM) or FSH and hCG-primed (in vivo maturation - VVM) and compared for the expression of mRNAs encoding follistatin (FST), inhibin, and activin receptors. The FST mRNA displayed marginally decreased expression (P = 0.05) in association with IVM in the granulosa cells. The ACVR1B mRNA was more highly expressed in cumulus cells with IVM compared to VVM. Cumulus-oocyte-complexes from FSH-primed monkeys exposed to exogenous follistatin during the 24 h IVM period exhibited no differences in the percentage of oocytes maturing to the MII stage compared to controls. However, embryos from these oocytes had significantly decreased development to the blastocyst stage. The effect of FST on early embryo culture was determined by exposing fertilized VVM oocytes to exogenous FST from 12 to 60 h post-insemination. FST significantly improved time to first cleavage and embryo development to the blastocyst stage compared to controls. The differential effects of exogenous FST on embryo development when administered pre and post oocyte maturation may depend on the endogenous concentration in cumulus cells and oocytes. These results reveal evolutionary conservation of a positive effect of FST on embryogenesis that may be broadly applicable to enhance in vitro embryogenesis, with potential application to human clinical outcome and livestock and conservation biology. Li et al. (1993) reported a stimulatory action of follistatin on progestin secretion in the human ovary, which is accompanied by an increased accumulation of intracellular cAMP levels. Follistatin may well be another potential regulator of steroid hormone production in human granulosa cells during the periovulatory period. Nakamura et al. (1990) reported that follistatin inhibits activin-induced differentiation of rat follicular granulosa cells in vitro. In a study in which 37 candidate genes were tested for linkage and association with PCOS or hyperandrogenemia in 150 families, Urbanek et al. (1999) found evidence for linkage between polycystic ovary syndrome and follistatin. Liao WX,et al 2000 screened 64 Chinese patients with PCOS for mutations in the entire coding region (including the region encoding alternative carboxy-terminals) of the follistatin gene using polymerase chain reaction (PCR)-based single-stranded conformational polymorphism (SSCP) and DNA sequencing. However, they could not identify a single mutation of either the activating or inhibiting type, using these techniques. Functional genomics studies of oocyte competence: evidence that reduced transcript abundance for follistatin is associated with poor developmental competence of bovine oocytes. Patel OV et al. Poor oocyte competence contributes to infertility in humans and livestock species. The molecular characteristics of such oocytes are generally unknown. Objectives of the present studies were to identify differences in RNA transcript abundance in oocytes and early embryos associated with reduced oocyte competence and development to the blastocyst stage. Microarray experiments were conducted using RNA isolated from germinal vesicle stage oocytes collected from adult versus prepubertal animals (model of poor oocyte competence). A total of 193 genes displaying greater mRNA abundance in adult oocytes and 223 genes displaying greater mRNA abundance in prepubertal oocytes were detected. Subsequent gene ontology analysis of microarray data revealed significant overrepresentation of transcripts encoding for genes in hormone secretion classification within adult oocytes and such genes were selected for further analysis. Real-time PCR experiments revealed greater abundance of mRNA for betaA and betaB subunits of inhibin/activin and follistatin, but not the alpha subunit in germinal vesicle stage oocytes collected from adult versus prepubertal animals. Cumulus cell follistatin and betaB subunit mRNA abundance were similar in samples collected from prepubertal versus adult animals. A positive association between time of first cleavage (oocyte competence) and follistatin mRNA abundance was noted. Follistatin, betaB, and alpha subunit mRNAs were temporally regulated during early bovine embryogenesis and peaked at the 16-cell stage. Collectively, results demonstrate a positive association of follistatin mRNA abundance with oocyte competence in two distinct models and dynamic regulation of follistatin, betaB, and alpha subunit mRNAs in early embryos after initiation of transcription from the embryonic genome. Molecular determinants of oocyte competence: Potential functional role for maternal (oocyte-derived) follistatin in promoting bovine early embryogenesis. Lee KB et al. Previous studies established a positive relationship between oocyte competence and follistatin mRNA abundance. Herein, we used the bovine model to test the hypothesis that follistatin plays a functional role in regulation of early embryogenesis. Treatment of early embryos with follistatin during in vitro culture (prior to embryonic genome activation) resulted in a dose dependent decrease in time to first cleavage, increased numbers of blastocysts and increased blastocyst total and trophectoderm cells numbers. To determine the requirement of endogenous follistatin for early embryogenesis, follistatin ablation/replacement studies were performed. Microinjection of follistatin siRNA into zygotes reduced follistatin mRNA and protein and was accompanied by a reduction in number of embryos developing to 8- to 16-cell and blastocyst stages and reduced blastocyst total and trophectoderm cell numbers. Effects of follistatin ablation were rescued by culture of follistatin siRNA injected embryos in the presence of exogenous follistatin. To investigate whether follistatin regulation of early embryogenesis is potentially mediated via inhibition of endogenous activin activity, the effects of treatment of embryos with exogenous activin, SB-431542 (inhibitor of activin, TGF-beta and nodal type I receptor signaling) and follistatin + SB-431542 were investigated. Activin treatment mimicked positive effects of follistatin on time to first cleavage and blastocyst development, whereas negative effects of SB-431542 treatment were observed. Stimulatory effects of follistatin on embryogenesis were not blocked by SB-431542 treatment. Results support a functional role for oocyte-derived follistatin in bovine early embryogenesis and suggest that observed effects of follistatin are likely not mediated by classical inhibition of activin activity. | ||||
| Expression regulated by | FSH, LH, Growth Factors/ cytokines, TGF | ||||
| Comment | Expression, Regulation, and Functional Characterization of FST Gene in Porcine Granulosa Cells. Zhou Q et al. (2016) Proliferation, differentiation, and estrogen secretion of granulosa cells are the key factors affecting the estrous after weaning in sows. The objective of this study was to evaluate the expression of Follistatin (FST) in the ovary of Xiushui Hang and Duroc sows at weaning and estrus, the effect of FSH on transcript abundance of FST gene in granulosa cells and the role of FST gene in the weaning to estrus using siRNAs targeted to FST gene. In the present study, expression of the FST mRNA was evaluated by real time PCR. The FST mRNA levels showed a reduction from weaning to the estrus in both Xiushui Hang and Duroc sows, and the mRNA levels in Duroc ovary was higher than in Xiushui Hang sows at the beginning of estrus. Granulosa cells were obtained from the two largest follicles around follicular deviation, FST expression was decreased sharply after treatment with FSH (250 ng/ml). Knockdown of FST by siRNA in porcine granulosa cells significantly increased cell proliferation and estrogen secretion. These results indicate that FST gene is a negative regulator of follicle growth and function during the weaning-estrus interval.////////////////// FOXL2 and BMP2 Act Cooperatively to Regulate Follistatin Gene Expression during Ovarian Development. Kashimada K et al. Follistatin is a secreted glycoprotein required for female sex determination and early ovarian development, but the precise mechanisms regulating follistatin (Fst) gene expression are not known. Here, we investigate the roles of bone morphogenetic protein 2 (BMP2) and forkhead-domain transcription factor L2 (FOXL2) in the regulation of Fst expression in the developing mouse ovary. Bmp2 and Fst showed similar temporal profiles of mRNA expression, whereas FOXL2 protein and Fst mRNA were coexpressed in the same ovarian cells. In a cell culture model, both FOXL2 and BMP2 up-regulated Fst expression. In ex vivo mouse fetal gonad culture, exogenous BMP2 increased Fst expression, but this effect was counteracted by the BMP antagonist Noggin. Moreover, in Foxl2-null mice, Fst expression was reduced throughout fetal ovarian development, and Bmp2 expression was also reduced. Our data support a model in which FOXL2 and BMP2 cooperate to ensure correct expression of Fst in the developing ovary. Further, Wnt4-knockout mice showed reduced expression of Fst limited to early ovarian development, suggesting a role for WNT4 in the initiation, but not the maintenance, of Fst expression. Shintani et al. (1997) used enzyme-linked immunosorbent assays (ELISA) for human follistatins (FS) to measure total immunoreactive (ir-) rat FS and free rat FS, and investigate the regulation of production of total ir-FS and free FS by rat granulosa cells (GC) in vitro. FS protein production by cultured undifferentiated rat GC is up-regulated by FSH and activin, possibly via both protein kinase A and C pathways. Tano et al. (1995) reported that follistatin mRNA accumulation was stimulated by FSH. 8-Br-cAMP and phorbol 12-myristate 13-acetate (PMA) induced a time-dependent increase in follistatin mRNA levels. A more dramatic stimulation of follistatin mRNA was observed when this culture was treated with activin, and follistatin also blocked the effect of activin on the follistatin mRNA. Tuuri et al reported that follistatin messenger ribonucleic acid and secreted protein levels are induced by chorionic gonadotropin in cultured human granulosa-luteal cells. Lindsell et al.(1993) reported the regulation of follistatin messenger ribonucleic acid in porcine granulosa cells by epidermal growth factor and the protein kinase-C pathway. Michel et al reported that follistatin mRNA levels in granulosa cells are regulated by FSH rather than LH, and that the stimulation by FSH can be inhibited by epidermal growth factor but enhanced by activin. Activin alone was also capable of stimulating follistatin mRNA. Transforming growth factor beta1 regulates follistatin mrna expression during in vitro bovine granulosa cell differentiation Fazzini M, et al . In order to test the hypothesis that transforming growth factor beta (TGF-beta) acts by FS regulation on bovine granulosa cells in in vitro differentiation, we analyzed the effect of TGF-beta1 on follistatin mRNA expression in three differentiation states of bovine granulosa cells. We showed a positive regulation of FS mRNA after TGF-beta1 (1 ng/ml) treatment of freshly isolated granulosa cells from small-medium antral follicles (2-8 mm). This effect was abolished by the addition of exogenous follistatin (100 ng/ml), suggesting that this effect could be mediated by activin. Although these cells showed a similar effect on FS mRNA expression after treatment with activin-A, a soluble form of activin receptor type IIA was unable to inactivate the TGF-beta effect. When we tested the TGF-beta effect on FS mRNA in different granulosa cell states, TGF-beta1 regulation was associated with progesterone production only in freshly isolated cells. The amount of total activin-A produced by first passage cells (dedifferentiated cells), was ten times smaller than the one measured in a conditioned medium from freshly isolated cells (mature cells). The TGF-beta1-dependent FS mRNA expression persisted in first passage cells without changes with FS addition. On the other hand, the BGC-1 granulosa cell line (immature cells) produced large amounts of activin-A regulated by TGF-beta1 and an invariable steady state of FS mRNAs. In summary, our results showed that FS mRNA expression is regulated by TGF-beta1 independently of activin effects in differentiated granulosa cells. | ||||
| Ovarian localization | Oocyte, Granulosa, Luteal cells | ||||
| Comment | Singh et al. (1998) localized follistatin using immunohistochemical labeling. Follistatin was distributed in the perinuclear cytoplasm of granulosa and luteal cells but not in theca cells. Dominant follicles contained more follistatin than corresponding subordinate follicles. The amount of follistatin was maximal during the mid-growing phase of the dominant follicle and decreased thereafter. Among the corpora lutea, the maximal amount was detected at mid-diestrus. Less than half of luteal cells displayed the stain for follistatin; positively stained luteal cells were located in close proximity to blood capillaries. Follistatin was not detectable in the corpus luteum during metestrus or proestrus. The degree of immunohistochemical expression of follistatin was phase specific for both follicles and corpora lutea. The most intense staining in follicles was associated with the period of functional dominance and in corpora lutea was seen during the phase of maximal development. Using a reverse transcription-polymerase chain reaction protocol, Sidis et al reported that follistatin mRNA was detectable in human but not mouse oocytes. Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization. | ||||
| Follicle stages | Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | Polymorphism of the follistatin gene in polycystic ovary syndrome. Jones MR et al. Follistatin has been reported as a candidate gene for polycystic ovary syndrome (PCOS) from linkage and association studies. Acting to regulate the development of ovarian follicles and as an antagonist to aromatase activity, alterations in follistatin function or expression may result in key features of PCOS such as reduced serum FSH, impaired ovarian follicle development and augmented ovarian androgen production. We investigated polymorphisms in the FST gene to determine if genetic variation is associated with susceptibility to PCOS or key phenotypic features of PCOS patients in a case-control association study. One hundred and seventy-three PCOS patients of Caucasian descent (mean age 30.0 +/- 4.8 years), conforming to the NIH diagnostic criteria, were recruited from a clinical practice database and 107 normal ovulating women (mean age 38.8 +/- 13.4 years) were recruited from the general community as control subjects. Morphometric data, biochemistry and genomic DNA were collected from study subjects and genotyping was performed on seven Single nucleotide polymorphisms (SNPs) in the FST gene region. Allele frequencies of the SNPs were rs1423560 G/C (0.99/0.01), rs3797297 C/A (0.80/0.20), rs11745088 C/G (0.98/0.02), rs3203788 A/T (0.98/0.02) and rs1062809 G/C (1.00/-), rs1127760 A/T (0.98/0.02) and rs1127761 A/T (0.98/0.02), and these were not significantly different between the PCOS and control groups (P < 0.05). Statistical analysis revealed significant associations between the SNP rs3797297 and sex hormone-binding globulin (P = 0.04) and free androgen index (FAI) (P < 0.01). We conclude that FST is not a susceptibility locus for PCOS; however, the SNP rs3797297 from FST gene was associated with androgenic markers for PCOS and may be of importance in the hyperandrogenaemia of the disease. | ||||
| Phenotypes | |||||
| Mutations |
5 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: None
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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