| inhibin subunit alpha | OKDB#: 145 |
| Symbols: | INHA | Species: | human | ||
| Synonyms: | Locus: | 2q35 in Homo sapiens |
|
For retrieval of Nucleotide and Amino Acid sequences please go to:
OMIM
Entrez Gene
Mammalian Reproductive Genetics Endometrium Database Resource Orthologous Genes UCSC Genome Browser GEO Profiles new! Amazonia (transcriptome data) new! R-L INTERACTIONS MGI |
| 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 multiple peptide products, including the alpha subunit of the inhibin A and B protein complexes. These complexes negatively regulate follicle stimulating hormone secretion from the pituitary gland. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. Mutations in this gene may be associated with male infertility and premature ovarian failure in female human patients. [provided by RefSeq, Aug 2016] |
||||
| General function | Ligand, Hormone, Cytokine, Cell death/survival, Apoptosis, Cell cycle regulation, Tumor suppressor | ||||
| Comment | Mason et al. (1986) isolated cDNAs for the 3 inhibin subunits. These beta subunits share extensive sequence homology with transforming growth factor-beta. Wiater E,et al reported that inhibin is an antagonist of bone morphogenetic protein signaling. Inhibins are endogenous antagonists of activin signaling, long recognized as important regulators of gonadal function and pituitary FSH release. Inhibin, in concert with its co-receptor, betaglycan, can compete with activin for binding to type II activin receptors and, thus, prevent activin signaling. Because bone morphogenetic proteins (BMPs) also utilize type II activin receptors, we hypothesized that BMP signaling might also be sensitive to inhibin blockade. Here we show that inhibin blocks cellular responses to diverse BMP family members in a variety of BMP-responsive cell types. Inhibin abrogates BMP-induced Smad signaling and transcription responses. Inhibin competes with BMPs for type II activin receptors, and this competition is facilitated by betaglycan. Betaglycan also enables inhibin to bind to and compete with BMPs for binding to the BMP-specific type II receptor BMPRII, which does not bind inhibin in the absence of betaglycan. Betaglycan can confer inhibin responsiveness on cells that are otherwise insensitive to inhibin. These findings demonstrate that inhibin, acting through betaglycan, can function as an antagonist of BMP responses, suggesting a broader role for inhibin and betaglycan in restricting and refining a wide spectrum of transforming growth factor beta superfamily signals. | ||||
| Cellular localization | Secreted | ||||
| Comment | |||||
| Ovarian function | Follicle development, Preantral follicle growth, Antral follicle growth, Steroid metabolism | ||||
| 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.////////////////// RNAi-mediated knockdown of inhibin α subunit increased apoptosis in granulosa cells and decreased fertility in mice. Kadariya I et al. (2015) Inhibin α (INHα), a member of TGFβ superfamily, is an important modulator of reproductive function that plays a vital role in follicular changes, cell differentiation, oocyte development, and ultimately in mammalian reproduction. However, the role of inhibin α in female fertility and ovarian function remains largely unknown. To define its role in reproduction, transgenic mice of RNAi-INHα that knock down the INHα expression by shRNAi were used. Inhibin α subunit gene was knocked down successfully at both transcriptional and translational levels by RNAi PiggyBac transposon (Pbi) mediated recombinant pshRNA vectors and purified DNA fragments were microinjected into mouse zygotes. Results showed that transgenic female mice were sub-fertile and exhibited 35.28% reduction in litter size in F1 generation relative to wild type. The decreased litter size associated with the reduction in the number of oocytes ovulated after puberty. Serum INHα level was significantly decreased in both 3 and 6 weeks; whereas, FSH was significantly increased in 3 weeks but not in 6 weeks. Furthermore, suppression of INHα expression significantly promoted apoptosis by up-regulating Caspase-3, bcl2, INHβB and GDF9 and down regulated Kitl and TGFβRIII genes both at transcriptional and translational levels. Moreover, it also dramatically reduced the progression of G1 phase of cell cycle and the number of cells in S phase as determined by flow cytometer. These results indicate that suppression of INHα expression in RNAi-transgenic mice leads to disruption of normal ovarian regulatory mechanism and causes reproductive deficiencies by promoting cellular apoptosis, arresting cellular progression and altering hormonal signaling.////////////////// 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. Hillier et al. (1993) reported that inhibin exerts potent and selective stimulation of human thecal cell androgen synthesis in vitro. Forage et al. (1987) demonstrate that neutralization of inhibin can be effected by immunization with bovine inhibin alpha subunit and that such immunization results in increased ovulation rates as predicted from the biological role of inhibin as a suppressor of FSH. | ||||
| Expression regulated by | FSH, LH, Steroids, Growth Factors/ cytokines, Eicosanoids | ||||
| Comment | Recombinant BMP4 and BMP7 increase activin A production by up-regulating inhibin βA subunit and furin expression in human granulosa-lutein cells. Chang HM et al. (2015) Context: Granulosa cell-derived activins play important roles in the regulation of ovarian functions. To date, there is limited information pertaining to the intracellular regulation, assembly and secretion of endogenous activin A in human granulosa cells. Objective: The aim of this study was to examine the effects of BMP4 and BMP7 on furin expression and activin A production as well as the underlying mechanisms of action in human granulosa cells. Design: An established immortalized human granulosa cell line (SVOG) and primary granulosa-lutein cells were used as study models. Expression of inhibin subunits and furin as well as activin A accumulation were examined after exposure to recombinant human BMP4 or BMP7. A BMP type I receptor inhibitor (dorsomorphin), a furin inhibitor (Dec-RVKR-CMK), and small interfering RNAs targeting SMAD4 and furin were used to verify the specificity of the effects and investigate potential mechanisms. Setting: The study was conducted in an academic center. Main Outcome Measures: Specific mRNA and protein levels were examined using real time-quantitative PCR and Western blot. Activin A levels were measured using enzyme immunoassay. Results: Treatment with BMP4 and BMP7 significantly increased furin mRNA and protein, inhibin βA mRNA and activin A accumulation. Pre-treatment with dorsomorphin or SMAD4 knockdown reversed the stimulatory effects of BMP4 and BMP7 on furin and inhibin βA expression. In addition, furin knockdown or pre-treatment with a furin inhibitor attenuated the BMP4- and BMP7-induced accumulation of activin A. Conclusion: Recombinant BMP4 and BMP7 increase the production of bioactive mature activin A by up-regulating both the production and proteolytic processing of inhibin βA subunit in human granulosa cells. The enhancement of inhibin βA subunit processing is attributable to a SMAD-dependent up-regulation of its proprotein convertase, furin. These findings provide a potential mechanism by which theca cells can regulate neighboring granulosa cells in the ovary.////////////////// DNA Methylation and Histone Modifications Are Associated with Repression of the Inhibin a Promoter in the Rat Corpus Luteum. Meldi KM et al. The transition from follicle to corpus luteum after ovulation is associated with profound morphological and functional changes and is accompanied by corresponding changes in gene expression. The gene encoding the a subunit of the dimeric reproductive hormone inhibin is maximally expressed in the granulosa cells of the preovulatory follicle, is rapidly repressed by the ovulatory LH surge, and is expressed at only very low levels in the corpus luteum. Although previous studies have identified transient repressors of inhibin a gene transcription, little is known about how this repression is maintained in the corpus luteum. This study examines the role of epigenetic changes, including DNA methylation and histone modification, in silencing of inhibin a gene expression. Bisulfite sequencing reveals that methylation of the inhibin a proximal promoter is low in preovulatory and ovulatory follicles but is elevated in the corpus luteum. Increased methylation during luteinization is observed within the cAMP response element in the promoter, and EMSA demonstrate that methylation of this site inhibits cAMP response element binding protein binding in vitro. Chromatin immunoprecipitation reveals that repressive histone marks H3K9 and H3K27 trimethylation are increased on the inhibin a promoter in primary luteal cells, whereas the activation mark H3K4 trimethylation is decreased. The changes in histone modification precede the alterations in DNA methylation, suggesting that they facilitate the recruitment of DNA methyltransferases. We show that the DNA methyltransferase DNMT3a is present in the ovary and in luteal cells when the inhibin a promoter becomes methylated and observe recruitment of DNMT3a to the inhibin promoter during luteinization. The hormonal regulation of inhibin production by cultured granulosa cells from immature hypophysectomized, estrogen-treated rats was examined using a specific RIA by Bicsak et al. (1986) Granulosa cell inhibin secretion is stimulated by FSH and LH but not by PRL, presumably via a cAMP-mediated pathway. Bergada I, et al 2000 reported the role of inhibins in childhood and puberty. The determination of serum dimeric inhibins from birth through adulthood reflects a distinct pattern of both inhibins in males and females. Concomitantly with the gonadotrophin surge, an important production of inhibin B is observed during the first months of life. In girls, high serum levels of inhibin A are observed during the first two months of life; thereafter, they are undetectable until puberty. An active secretion of inhibin B persists in both males and females in the period of maximal LHRH pulse generator restraint; however, the possible gonadotrophin dependence of this production remains controversial. At puberty, a progressive rise in serum inhibin B occurs concomitantly with the increased production of sex steroids in both males and females. A similar secretion pattern of inhibin A is observed in girls. This increment is mainly exerted by gonadotrophins and modulated by multiple paracrine/autocrine mechanisms within the ovary and the testis that regulate the dimerization of the inhibin subunits throughout pubertal maturation. The differences observed in males and females between circulating dimeric inhibins in relation to gonadotrophins and sex steroid concentrations from birth through puberty has opened a new perspective for research in human reproduction. | ||||
| Ovarian localization | Granulosa, Luteal cells | ||||
| Comment | Meunier et al (1989) studied immature female rats treated with PMSG and human CG to induce ovulation for inhibin subunit mRNA localization. Administration of PMSG led to a sharp increase in the expression of all three subunits in large preovulatory follicles whereas injection with human CG caused a decrease in the levels of the respective mRNAs. In contrast to mature females, shortly before ovulation, levels of inhibin alpha-subunit mRNA were low in small antral follicles. In addition, at that time, inhibin beta A- and beta B-subunits mRNAs were present in several large follicles (greater than 500 microns). More than 2 days after ovulation, inhibin beta A- and beta B-subunit mRNAs could not be detected in small antral size follicles of hormonally induced females. On the other hand, hybridization signals for the inhibin alpha-subunit were observed in some small antral and preantral size follicles, while signals were very low or undetectable in a large number of atretic follicles. Smith et al. (1991) reported that the human corpus luteum is a significant source of immunoreactive inhibin during the normal human menstrual cycle. The specific localization within the granulosalutein cells of the corpus luteum suggests that inhibin alpha-subunit production may originate from a discrete cell population within the human corpus luteum. Lappohn et al. (1989) summarized data on the use of inhibin as a marker for granulosa-cell tumors. Danforth et al. (1998) reported that luteal phase inhibin-a and follicular phase inhibin-b were correlated inversely with age in perimenopausal women. In addition, luteal phase inhibin-a and follicular phase inhibin-b levels were correlated inversely with follicular phase FSH levels. These direct measures of ovarian function may be more sensitive indicators of "ovarian reserve" than indirect indicators such as pituitary FSH secretion. 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 | Hsu et al. (1995) reported that different 5'-flanking regions of the inhibin-alpha gene target transgenes to the gonad and adrenal in an age-dependent manner in transgenic mice. Kananen et al. (1995) reported gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/simian virus T-antigen fusion gene and the establishment of gonadotropin-responsive granulosa cell lines. | ||||
| Phenotypes |
POF (premature ovarian failure) |
||||
| Mutations |
6 mutations
Species: mouse
Species: human
Species: mouse
Species: human
Species: porcine
Species: human
|
||||
| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
|
| created: | Sept. 25, 1999, midnight | by: |
Hsueh email:
home page: |
| last update: | March 19, 2020, 1:19 p.m. | by: | hsueh email: |
Click here to return to gene search form