Transforming growth factor-beta is a multifunctional cytokine known to modulate several tissue development and repair
processes, including cell differentiation, cell cycle progression, cellular migration, adhesion, and extracellular matrix
addition to type I TGF-beta receptor (TGFBR1) and type II (TFGBR2), type III (TGFBR3) has been
identified. It is a glycoprotein that binds TGF-beta and exists in both a membrane-bound and a soluble form. It may
serve as a receptor accessory molecule in both the TGF-beta and fibroblast growth factor systems.
Lewis et al. (2000) demonstrated that the type III TGF-beta receptor, or beta-glycan, can function as an inhibin coreceptor with ActRII. Beta-glycan binds inhibin with high affinity and enhances binding in cells
coexpressing ActRII and beta-glycan. Inhibin also forms crosslinked complexes with both recombinant and
endogenously expressed beta-glycan and ActRII.
Expression of betaglycan, an inhibin coreceptor, in normal human ovaries and ovarian sex cord-stromal tumors and its regulation in cultured human granulosa-luteal cells
Liu J,et al .
Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. Furthermore, betaglycan expression was detected in the vast majority of granulosa cell tumors, thecomas, and fibromas, with weaker staining in granulosa cell tumors compared with fibrothecomas. In cultured granulosa-luteal cells, FSH and LH treatment increased dose-dependently the accumulation of betaglycan mRNA, as did the protein kinase A activator dibutyryl cAMP and the protein kinase C inhibitor staurosporine. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.
Effect of Follicle-stimulating Hormone and Estrogen on the Expression of Betaglycan Messenger Ribonucleic Acid levels in Cultured Rat Granulosa Cells Omori Y, et al .
Betaglycan (TGF-betatype III receptor) was recently identified as a coreceptor to enhance the binding of inhibin A to activin type II receptor. This inhibin/betaglycan/activin type II receptor complex prevents activins from binding to their own receptors. The present study was undertaken to identify the expression and the regulation of the betaglycan gene in cultured rat granulosa cells. Northern blot analysis indicated betaglycan mRNA transcript of approximately 6.4 kbp. The treatment of the cells with FSH increased the betaglycan mRNA level, and a concurrent treatment with estradiol brought a significant increase in betaglycan mRNA. The protein kinase A activator, 8-Br cAMP, also increased the expression of its mRNA. Furthermore, betaglycan mRNA was induced additively by estradiol, which was blocked by estrogen receptor antagonists (ICI 182780, R, R-THC). In the Luciferase assay, FSH altered the promoter activity of betaglycan. Moreover, when FSH plus estradiol was added to the granulosa cells, a significant increase in the half-life of betaglycan mRNA transcript was seen. In summary, FSH and estradiol increased betaglycan mRNA expression, most possibly through the protein kinase A pathway and the estrogen receptor beta. The increase of betaglycan mRNA was due to an increase in transcription and altered mRNA stability. In ovarian regulatory function, the expression of betaglycan may involve the functional antagonism of inhibin A in activin signal transduction.
Goddard I, et al 1995 identified and characterized transforming growth factor beta receptor expression in cultured porcine
granulosa cells through three different
approaches including cross-linking experiments, Western- and Northern-blotting
analysis. In cross-linking experiments, labeled TGF beta was shown to bind to
four different molecular species of 300, 168, 72 and 58 kDa. The 300-kDa
species may correspond to beta-glycan, while the 72- and 58-kDa correspond to
TGF beta type II and I receptors, respectively. The presence of these receptors
was further demonstrated by Western-blotting analysis using specific polyclonal
antibodies. Finally, both the expression of beta-glycan, type II and type I mRNA,
was confirmed through Northern-blotting analysis as shown by the presence of
6.4, 4.6 and 5.8 kb mRNA, respectively.
Roelen BA, et al 1998 reported that both TGF-beta receptor type I and II mRNAs were found to be
expressed in bovine oocytes and preimplantation two-cell, four-cell, eight-cell,
morula-, and blastocyst-stage embryos, as determined by heminested reverse transcription polymerase chain reaction (RT-PCR). The mRNA expression patterns of TGF-beta receptor types I, II, and III in a variety of bovine organ
tissues were examined by Northern blot hybridization, and highest levels were
detected in lung and ovary.
Differential expression of TGFBR3 (betaglycan) in mouse ovary and testis during gonadogenesis. Sarraj MA et al. TGFBR3 is an accessory receptor that binds to and modulates the activities of both transforming growth factor-beta (TGFbeta) and inhibin, two members of the TGFbeta superfamily of growth factors that regulate many aspects of reproductive biology. Tgfbr3 is known to be expressed in adult testis and ovary, but little is known about this receptor during gonadogenesis. Herein, we describe Tgfbr3 expression in the male and female fetal and neonatal murine gonad. Real-time PCR analysis revealed that Tgfbr3 mRNA was expressed at higher levels in the developing testis compared to ovary. TGFBR3 was expressed within the fetal testis interstitium, predominantly by Leydig cells, but expression shifted inside the seminiferous cords at birth. In contrast, TGFBR3 was detected in both the somatic and germ cell lineages in the fetal and neonatal ovary. This differential expression pattern suggests divergent roles for this TGFBR3 in developing testis and ovary.
Secondary, Antral, Preovulatory, Corpus luteum
Aberrantly increased mRNA expression of betaglycan, an inhibin co-receptor in the ovarian tissues in women with polycystic ovary syndrome. Zhu R et al. Aim: To compare the gene expressional levels of receptors for activins and inhibins in ovarian tissues between women with polycystic ovary syndrome (PCOS) and normal controls, and to analyze their biologically relevant associations with serum hormone levels. Methods: Total RNA of ovarian tissues from PCOS (n = 14) and normal controls (n = 21) were isolated during the follicular phase of the menstrual cycle. Real-time PCRs were performed to examine the relative mRNA expression levels of the activin receptors, including activin receptor type IA (ActRIA), type IB (ActRIB), type IIA (ActRIIA), and type IIB (ActRIIB), and the inhibin receptors, betaglycan and an inhibin binding protein (InhBP/p120). At the same time, the serum levels of estradiol (E(2)), testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B and activin A were measured. Results: The PCOS patients showed endocrine characteristics with higher concentrations of LH, T and inhibin B, and a lower concentration of activin A. Real-time PCR demonstrated that the relative expression level of betaglycan against that of GAPDH was increased 1.5-fold in the ovarian tissues during the follicular phase of PCOS patients when compared with normal controls, while the activin receptors ActRIA, ActRIB, ActRIIA, ActRIIB, and the inhibin co-receptor InhBP/p120 were unchanged. Moreover, the betaglycan mRNA expression showed biologically relevant associations with serum FSH, LH, E(2) and inhibin B levels in both the PCOS and normal controls. Conclusions: This is the first report to demonstrate the aberrantly increased expression of betaglycan mRNA in PCOS ovaries. The mechanism by which betaglycan contributes to the pathologic process of PCOS remains to be clarified.
Lewis et al. (2000) reported immunostaining for granulosa and theca cells as well as the oocyte. Leigh A. MacConell, et al 2002 reported the Distribution of Betaglycan Protein and mRNA in Rat
Brain, Pituitary, and Gonads: Implications for a Role for
Betaglycan in Inhibin-Mediated Reproductive Functions
Moderate levels of mRNA were observed in ovarian granulosa cells, with lower expression in
the thecal layer and the oocyte. In the testes, betaglycan mRNA was observed in the Leydig and tubule-specific germ cells.
This is the first comprehensive report detailing the distribution of betaglycan in mammalian reproductive tissues. The
present findings illustrate and support the hypothesis of a modulatory role for betaglycan in TGF?and/or inhibin effects in
POF (premature ovarian failure)
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Identification of novel missense mutations of the TGFBR3 gene in Chinese women with premature ovarian failure. Qin CR et al. The aim of this study was to assess the association between human transforming growth factor receptor, type III (TGFBR3) and idiopathic premature ovarian failure (POF) in a Chinese population. A total of 112 Chinese women with idiopathic POF and 110 normal controls were examined. DNA samples prepared from blood leukocytes were used as templates for polymerase-chain reaction amplification of DNA fragments from TGFBR3. The gene fragments were sequenced. Web-based programs, including PolyPhen, Sorting Intolerant from Tolerant (SIFT), Prediction of Pathological Mutations (PMUT), ScanProsite and ClustalW2, were used to predict the potential functional and structural impacts of the missense variants of TGFBR3. A total of 11 novel variants were identified. Among them, six were found only in the POF patients. Two missense variants, p.E459G and p.P825L, which are conserved in primates, were predicted to have functional and structural impacts on the TGFBR3 protein. The other four variants (c.381+12A>C, c.2431-7A>G, p.S172S and p.C220C) were considered benign. However, further functional studies are necessary to confirm these findings. The causes of premature ovarian failure are diverse and largely idiopathic. Down-regulation of the FSH concentrations by inhibins is mediated through its receptor, human transforming growth factor receptor, type III (TGFBR3) in the gonadotrophs. The aim of this study was to assess the association between human TGFBR3 and idiopathic POF in a Chinese population. Web-based programs, including PolyPhen, Sorting Intolerant from Tolerant (SIFT), Prediction of Pathological Mutations (PMUT), ScanProsite and ClustalW2, were used to predict the potential functional and structural impacts of two novel missense variants, p.E459G and p.P825L, on the TGFBR3 protein. These mutations were predicted to have functional impacts on the protein and are likely to be pathogenic. However, further functional studies are necessary to confirm these findings.