Bone morphogenetic proteins (BMPs) are a family of proteins that induce bone formation at extracellular sites in vivo.
BMPs act on osteoblasts and chondrocytes as well as other cell types, including neurocells, and they play important
roles in embryonal development. Members of the BMP family include BMP1 to BMP6, BMP7), also called
osteogenic protein-1 (OP1), OP2 (BMP8), and others. BMPs belong to the transforming growth factor beta (TGF-beta)
superfamily, which includes, in addition to the TGF-betas (e.g., 190180), activin/inhibins (e.g., alpha-inhibin),
mullerian inhibiting substance , and glial cell line-derived neurotrophic factor . TGF-betas and
activins transduce their signals through the formation of heteromeric complexes of 2 different types of serine (threonine)
kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind
ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I
receptors require their respective type II receptors for ligand binding.
Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5. Mazerbourg S 2004 et al.
Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the TGF-beta superfamily that includes TGF-beta, activin, and bone morphogenetic proteins (BMPs). GDF-9 is indispensable for the development of ovarian follicles from the primary stage, and treatment with GDF-9 enhances the progression of early follicles into small preantral follicles. Similar to other TGF-beta family ligands, GDF-9 likely initiates signaling mediated by type I and type II receptors with serine/threonine kinase activity, followed by the phosphorylation of intracellular transcription factors named Smads. We have shown previously that GDF-9 interacts with the BMP type II receptor (BMPRII) in granulosa cells, but the type I receptor involved is unknown. Using P19 cells, we now report that GDF-9 treatment stimulated the CAGA-luciferase reporter known to be responsive to TGF-beta mediated by the type I receptor, activin receptor-like kinase (ALK)5. In contrast, GDF-9 did not stimulate BMP-responsive reporters. In addition, treatment with GDF-9 induced the phosphorylation of Smad2 and Smad3 in P19 cells, and the stimulatory effect of GDF-9 on the CAGA-luciferase reporter was blocked by the inhibitory Smad7, but not Smad6. We further reconstructed the GDF-9 signaling pathway using Cos7 cells that are not responsive to GDF-9. After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay. The roles of ALK5 and downstream pathway genes in mediating GDF-9 actions were further tested in ovarian cells. In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3. Furthermore, transfection with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 actions. In conclusion, although GDF-9 binds to the BMP-activated type II receptor, its downstream actions are mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins. Because ALK5 is a known receptor for TGF-beta, diverse members of the TGF-beta family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways.
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NCBI Summary:
This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are BMPs, which are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, Jul 2008]
Inhibition of Oocyte Growth Factors In Vivo Modulates Ovarian Folliculogenesis in Neonatal and Immature Mice. Myllymaa S et al. Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are among the key regulators transmitting the signaling between the oocyte and the surrounding granulosa cells. Previously it has been shown that a recombinant bone morphogenetic protein type II -receptor ectodomain -Fc fusion protein (BMPRIIecd-Fc) is able to inhibit the actions of GDF9 and BMP15 in vitro. Here we have produced bioactive BMPRIIecd-Fc which was intraperitoneally injected into neonatal mice. Early folliculogenesis was first studied by injecting mice five times with various doses of the BMPRIIecd-Fc during the postnatal days 4-12. Folliculogenesis was affected dose-dependently, as evidenced by a decreased mitogenesis of granulosa cells of the growing follicles. Furthermore, we also noticed a decrease in the number of secondary and tertiary follicles as well as an increase in the oocyte size. Electron microscopic analysis revealed that the ultrastructure of the granulosa cells of the primary follicles was not affected by the BMPRIIecd-Fc treatment. A second study was conducted to investigate whether a longer treatment with twelve injections during postnatal days 4-28 would inhibit folliculogenesis. Similar effects were obtained in the two studies on the early follicular development stages. However, in the long term study later stages of folliculogenesis were not blocked but rather increased number of antral follicles, preovulatory follicles and corpora lutea were found. We conclude that the BMPRIIecd-Fc is a potent modulator of ovarian folliculogenesis in vivo, and thus, is a valuable tool for studying the physiology and down-stream effects of oocyte-derived growth factors in vivo.
Vitt UA, et al 2002 reported that Bone Morphogenetic Protein Receptor Type II Is a Receptor for Growth Differentiation Factor-9.
Growth differentiation factor-9 (GDF-9) is a glycoprotein secreted by the oocyte that is capable of stimulating granulosa cell proliferation and inhibiting differentiation. GDF-9 is a member of the transforming growth factor beta superfamily of ligands known to signal through type I and II serine/threonine kinase receptors. In the sequenced human genome, seven type I and six type II receptors have been identified. Based on phylogenetic and sequence analyses, the author predicted that GDF-9 likely interacts with known type I and type II receptors and obtained soluble chimeric proteins with the ectodomains of candidate receptors fused to the Fc portion of immunoglobin and tested their ability to act as functional antagonists. Addition of bone morphogenetic protein receptor type II (BMPRII) ectodomain was most effective in blocking GDF-9 stimulation of granulosa cell proliferation and GDF-9 suppression of FSH-stimulated progesterone production. In addition, the ectodomains of bone morphogenetic protein receptor type IA, bone morphogenetic protein receptor type IB, and activin receptor type IIA were partially effective in blocking GDF-9 action. Furthermore, the BMPRII ectodomain directly interacted with GDF-9 in a coprecipitation study demonstrating the role of the BMPRII ectodomain as a binding protein for GDF-9. To demonstrate the role of BMPRII in GDF-9 signaling in follicular cells, the expression of this protein was blocked in cultured granulosa cells using specific BMPRII antisense oligomers. Inhibition of BMPRII biosynthesis completely prevented the GDF-9 induction of granulosa cell thymidine incorporation. GDF-9 expression is essential for early follicle development, and the presence of the type II and type I receptors in the neonatal rat ovary was verified by reverse transcription polymerase chain reaction. These results demonstrate the important role of BMPRII in mediating GDF-9 action in granulosa cells from small antral follicles and indicate that the effects of GDF-9 might be transduced by binding to BMPRII and one or more type I receptors.
Shimasaki S, et al 1999 reported that a functional bone morphogenetic protein system exists in the ovary.
In situ hybridization histochemistry identified strong mRNA labeling for BMP-4 and -7 in the theca cells and BMP receptor types IA, IB, and
II in the granulosa cells and oocytes of most follicles in ovaries of normal cycling
rats.
Souza CJH, et al 2002 reported the effect of bone morphogenetic protein 2 (BMP2) on oestradiol and
inhibin A production by sheep granulosa cells, and localization
of BMP receptors in the ovary by immunohistochemistry.
The bone morphogenetic proteins (BMPs) have been implicated in the paracrine
regulation of ovarian follicular development. In this study, we investigated
the expression of the BMP receptors (BMPRs) in sheep ovaries by
immunohistochemistry and the effect of BMP2, a natural ligand for these
receptors, on granulosa cells cultured in vitro. Ovaries from cyclic ewes were
fixed, embedded in paraffin wax and cut into sections. The sections were
rehydrated, submitted to microwave antigen retrieval and treated with
polyclonal antibodies against BMPR1A, BMPR1B and BMPR2. Strong immunostaining
for all three receptors was observed in the granulosa cell layer of follicles
from the primary to late antral stages of development. Staining was also
present in the oocyte, corpus luteum, ovarian surface epithelium and, to a
lesser extent, the theca layer of antral follicles. For functional studies,
granulosa cells were obtained from immature follicles 1-3 mm in diameter. The
cells were cultured for 6 days in serum-free medium containing 1 ng oFSH-20
ml(-1) in the presence of 0, 3, 10 or 30 ng ml(-1) human recombinant BMP2. The
medium was replaced every 2 days and oestradiol and inhibin A concentrations
were measured in the spent medium. in the absence of BMP2, oestradiol and
inhibin A production increased as the granulosa cells differentiated in vitro.
The addition of the highest dose of BMP2 enhanced oestradiol production (P <
0.05) without affecting the proliferation of the cells. It is concluded that
BMP receptors are present in sheep ovaries and that BMPs may have a role in
the differentiation of granulosa cells by enhancing the action of FSH.
Follicle stages
Antral
Comment
Differential expression of mRNAs encoding BMP/Smad pathway molecules in antral follicles of high- and low-fecundity Hu sheep. Xu Y et al. The Hu sheep is world-famous for its hyper-prolificacy and the bone morphogenetic protein (BMP)/Smad pathway and several other closely related molecules (GDF9, TGF-betaRI) have been shown to have a close relationship with reproduction in sheep. In order to investigate the mechanism of high fecundity in Hu sheep and its relationship with the BMP/Smad pathway, 147 Hu sheep were blood sampled for detection of the FecB mutation (A746G) in the BMPRIB gene by PCR-SSCP, and sixteen adult Hu ewes classified as either high-fecundity (HF) or low-fecundity (LF) animals were sacrificed for tissue and antral follicle sampling. The tissue distribution patterns of mRNAs encoding BMP/Smad pathway molecules including BMPs (BMP2, BMP4, BMP6, BMP7 and BMP15), BMP receptors (BMPRIA, BMPRIB and BMPRII), intracellular transducers (Smad1, Smad5 and Smad4) and closely related molecules (GDF9 and TGF-betaRI) were detected by RT-PCR and the gene expression levels in antral follicles were investigated by real-time PCR. The results showed that all experimental animals were homozygous for the BMPRIB (A746G) mutation, and all detected genes related to the BMP/Smad pathway and GDF9 and TGF-betaRI were expressed in the ovary. In addition, BMP4, BMPRIB, BMPRII, Smad4, GDF9 and TGF-betaRI mRNAs were more abundant in the antral follicles of HF animals than those of LF animals (P<0.05), but BMP15 mRNA was less abundant (P<0.01). This suggests that there could be an unidentified genetic mutation in BMPRIB, or other unidentified genes and unknown factors, which controls ovarian number by changing the expression patterns of genes known to regulate ovulation rate via the BMP/Smad pathway and closely related molecules (GDF9 and TGF-betaRI).
Phenotypes
Mutations
1 mutations
Species: None
Mutation name: None
type: naturally occurring fertility: fertile Comment: Single nucleotide polymorphisms in the bovine genome are associated with the number of oocytes collected during ovum pick up. Santos-Biase WK et al. The number of follicles recruited in each estrous cycle has gained practical importance in artificial reproductive technology, as it determines the oocyte yield from ultrasound-guided ovum pickup for in vitro embryo production. We aimed to identify single nucleotide polymorphisms (SNPs) in bovine genes related to reproductive physiology and evaluate the association between the candidate SNPs and the number of oocytes collected from ultrasound-guided ovum pickup. We sequenced genomic segments of GDF9, FGF8, FGF10 and BMPR2 and identified seventeen SNPs in the Bos taurus and Bos indicus breeds. Two SNPs cause amino acid changes in the proteins GDF9 and FGF8. Three SNPs in GDF9, FGF8 and BMPR2 were genotyped in 217 Nelore cows (B. indicus), while two previously identified mutations in LHCGR and mitochondrial DNA (mtDNA) were genotyped in the same group. The polymorphisms in GDF9, FGF8, BMRP2 and LHCGR were significantly associated (P<0.01) with the number of oocytes collected by ovum pickup, whereas the SNP in the mtDNA was not. In addition, we estimated an allelic substitution effect of 1.13?0.01 (P<0.01) oocytes for the SNP in the FGF8 gene. The results we report herein provide further evidence to support the hypothesis that genetic variability is an important component of the number of antral follicles in the bovine ovary.