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General Comment |
Although activins were discovered by virtue of their capacity to stimulate the production of
follicle-stimulating hormone by the pituitary gland and inhibins were initially characterized as FSH
inhibitors, activins and inhibins are dimeric proteins that share a common subunit. There are 3 activins (A, B, and A-B),
comprising different combinations of 2 closely related beta subunits (beta-A/beta-A; beta-B/beta-B; and beta-A/beta-B,
respectively) and 2 inhibins (A and B), consisting of 1 beta-subunit and an inhibin-specific alpha subunit (alpha/beta-A
and alpha/beta-B). Activins impinge on a much broader spectrum of cells than do inhibins; however, in those systems in
which both proteins are functional, they have opposing biologic effects. Activins are members of a family of
polypeptide growth factors that includes also the transforming growth factors-beta,
mullerian duct-inhibiting substance, and several bone morphogenetic proteins.
Mathews and Vale (1991) cloned an activin receptor cDNA by use of a method that has been used to clone other
receptors, such as that for erythropoietin. The cloning was based on the ability of the receptor to bind a labeled ligand
following expression of a cDNA library in mammalian cells. The cDNA coded for a protein of 494 amino acids
comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase
domain with predicted serine/threonine specificity. On the basis of affinity-crosslinking studies, They identified 2 types of activin receptors. The type I receptor has a molecular size of 65 kD, while the molecular
size of the type II receptor is 85 kD.
NCBI Summary:
Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]
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Comment |
Regulation of ACVR1 and ID2 by cell-secreted exosomes during follicle maturation in the mare. da Silveira JC 2014 et al.
BACKGROUND
Ovarian follicle growth and maturation requires extensive communication between follicular somatic cells and oocytes. Recently, intercellular cell communication was described involving cell-secreted vesicles called exosomes (50-150 nm), which contain miRNAs and protein, and have been identified in ovarian follicular fluid. The goal of this study was to identify a possible role of exosomes in follicle maturation.
METHODS
Follicle contents were collected from mares at mid-estrous (~35 mm, before induction of follicular maturation) and pre-ovulatory follicles (30-34 h after induction of follicular maturation). A real time PCR screen was conducted to reveal significant differences in the presence of exosomal miRNAs isolated from mid-estrous and pre-ovulatory follicles, and according to bioinformatics analysis these exosomal miRNAs are predicted to target members belonging to the TGFB superfamily, including ACVR1 and ID2. Granulosa cells from pre-ovulatory follicles were cultured and treated with exosomes isolated from follicular fluid. Changes in mRNA and protein were measured by real time PCR and Western blot.
RESULTS
ACVR1 mRNA and protein was detected in granulosa cells at mid-estrous and pre-ovulatory stages, and real time PCR analysis revealed significantly lower levels of ID2 (an ACVR1 target gene) in granulosa cells from pre-ovulatory follicles. Exposure to exosomes from follicular fluid of mid-estrous follicles decreased ID2 levels in granulosa cells. Moreover, exosomes isolated from mid-estrous and pre-ovulatory follicles contain ACVR1 and miR-27b, miR-372, and miR-382 (predicted regulators of ACVR1 and ID2) were capable of altering ID2 levels in pre-ovulatory granulosa cells.
CONCLUSIONS
These data indicate that exosomes isolated from follicular fluid can regulate members of the TGFB/BMP signaling pathway in granulosa cells, and possibly play a role in regulating follicle maturation.
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Comment |
Eramaa M, et al 1995 reported the expression of activin receptor mRNAs in cultured human granulosa-luteal cells.
Northern blot analysis indicated that cultured human GL cells as well as
freshly isolated preovulatory granulosa cells express the specific mRNAs for all
currently known serine/threonine kinase activin receptors, i.e. activin receptors I,
IB, II, and IIB.
Izadyar F, et al reported immunohistochemical localization and mRNA expression of
activin, inhibin, follistatin, and activin receptor in bovine
cumulus-oocyte complexes (COC)during in vitro maturation.
Activin receptor immunoreactivity in cumulus cell membranes and
oolemma increased during oocyte maturation to maximum values at the end of
culture in most of the COCs. It is concluded that the consistent presence of activin
and the increase in activin receptor in cumulus cells and oocytes during in vitro
maturation indicate a paracrine and/or autocrine action for activin on bovine
oocyte maturation.
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Mutations |
2 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. de Sousa Lopes SM, et al .
Deletion of various bone morphogenetic proteins (BMPs) and their downstream Smads in mice have clearly shown that BMP signaling is essential for the formation of primordial germ cells (PGCs). However, the molecular mechanism through which this takes place is still unclear. Here, we demonstrate that BMP4 produced in the extraembryonic ectoderm signals through ALK2, a type I BMP receptor, in the visceral endoderm (VE) to induce formation of PGCs from the epiblast. Firstly, embryonic day 5.5-6.0 (E5.5-E6.0) embryos cultured on fibronectin formed PGCs in the presence of VE, but not in its absence. Secondly, Alk2-deficient embryos completely lacked PGCs and the heterozygotes had reduced numbers, resembling Bmp4-deficient phenotypes. Thirdly, expression of constitutively active ALK2 in the VE, but not in the epiblast, was sufficient to rescue the PGC phenotype in Bmp4-deficient embryos. In addition, we show that the requirement for the VE at E5.5-E6.0 can be replaced by culturing embryos stripped of VE on STO cells, indicating that STO cells provide or transduce signals necessary for PGC formation that are normally transmitted by the VE. We propose a model in which direct signaling to proximal epiblast is supplemented by an obligatory indirect BMP-dependent signal via the VE.
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Kevenaar ME et al. (2008) Polycystic ovaries display an increased number of pre-antral and antral follicles compared with normal ovaries, suggesting that early and late follicle development are disturbed. The pathophysiology of this process is poorly understood. Since the transforming growth factor beta family members, anti-Müllerian hormone (AMH) and bone morphogenetic proteins (BMPs), inhibit FSH sensitivity, their signalling may contribute to the aberrant follicle development in these women. Here, we investigated the role of ALK2, a type I receptor for AMH/BMP signalling, in PCOS using a genetic approach. Seven single nucleotide polymorphisms in the ACVR1 gene, encoding ALK2, were genotyped in 359 PCOS patients and 30 normo-ovulatory and 3543 population-based control women, and haplotypes were determined. Subsequently, the association of ACVR1 variants with ovarian parameters and hormone levels was investigated. The polymorphisms rs1220134, rs10497189 and rs2033962 and their corresponding haplotypes did not show different frequencies from controls, but were associated with AMH levels in PCOS women (P = 0.001, P = 0.002 and P = 0.007, respectively). Adjustment for follicle number revealed that the association with AMH levels was, in part, independent from follicle number, suggesting that variants in ACVR1 also influence AMH production per follicle. Genetic variation within ACVR1 is associated with AMH levels and follicle number in PCOS women, suggesting that ALK2 signalling contributes to the disturbed folliculogenesis in PCOS patients.//////////////////
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