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Comment |
The Attenuating Effect of the Intraovarian Bone Morphogenetic Protein 4 on Age-Related Endoplasmic Reticulum Stress in Chicken Follicular Cells. Yao J et al. (2020) In the poultry, only less than 5% primordial follicles in the ovary can develop into the prehierarchical follicles (PHFs) leading to progressive development, ovulation, and egg formation. This low rate of recruitment indicates a huge potential for improvement of the laying performance. A great reduction in egg production is caused by aging with extensive follicular atresia. In this study, age-related changes in the laying performance and ovarian status were compared between the peak-lay (D280) and aged (D580) chickens. Subsequently, a cross coculture of PHFs and granulosa cells (GCs) from D280 or D580 hens was adopted to reveal the mechanism of declined follicle development. Results showed that persistent endoplasmic reticulum (ER) stress in GCs of the aged hens was accompanied with intensified apoptosis. Bone morphogenetic protein 4 (BMP4) secreted by GCs of PHFs in D280 hens was capable of relieving ER stress and improving follicular dominance for selection in D580 hens. During this action, BMP4 reduced free calreticulin (CALR, an ER marker) content and attenuated cell apoptosis in PHFs of D580 hens via the PERK-CHOP-BCL2/caspase3 or CALR-Ca2+-BCL2-caspase12 pathway. Furthermore, BMP4 prevented follicular atresia by promoting production of steroid hormones to improve survival of GCs in PHFs from the aged hens. In conclusion, intensified ER stress and apoptosis occurred in GCs of PHFs in aged chickens, while BMP4 secreted by GCs was capable of improving follicular viability by alleviating ER stress to promote follicular development.//////////////////Bmp4 inhibits goose granulosa cell apoptosis via PI3K/AKT/Caspase-9 signaling pathway. Yuan J et al. (2018) Bone morphogenetic protein 4 (BMP4) has an important role in regulating cellular proliferation, differentiation and apoptosis. It, however, is still unclear as to the mechanisms by which BMP4 regulates the apoptosis of granulosa cells (GCs) in geese. In the present study, there was cloning of the full-length coding sequence of goose BMP4 gene, which consisted of 1212 nucleotides encoding 403 amino acids. Its deduced amino acid sequence comprised one signal peptide, one TGFβ pro-peptide and one mature peptide domain. Results from conducting the quantitative real-time PCR (qPCR) indicated the relative abundances of BMP4 mRNA in geese GCs increased gradually from the relative abundances in pre-hierarchical follicles that were 4 to 6 mm in diameter to that in the fifth largest (F5) follicle and then relative abundances of BMP4 mRNA decreased with further development as the largest (F1) follicle. Results from use of the TUNEL assay indicated that overexpression of the goose BMP4 gene suppressed GC apoptosis and this was confirmed when relative abundances of the CAD, Caspase-9 and Caspase-3 proteins were determined using western blotting. In addition, overexpression of the BMP4 gene induced phosphorylation of AKT, which was inhibited with use of the PI3K inhibitor, LY294002. Co-transfection of BMP4 and LY294002 resulted in increased relative abundances of Caspase-9 and CAD proteins but had no effect on that of Caspase-3. Taken together, these results suggested that expression of the BMP4 gene resulted in a reduction in Caspase-9 protein leading to inhibition of GC apoptosis via the PI3K/AKT signaling pathway in geese.//////////////////
The BMP4-Smad Signaling Pathway Regulates Hyperandrogenism Development in a Female Mouse Model. Liu Y et al. (2017) Polycystic ovary syndrome (PCOS) is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age. Most patients with PCOS have hyperandrogenism, caused by excess androgen synthesis. Bone morphogenetic protein 4 (BMP4) is an essential regulator of embryonic development and organ formation, and recent studies have also shown that BMP4 may be involved in female steroidogenesis process. However, effect of BMP4 on hyperandrogenism remains unknown. Here, using a female mouse model of hyperandrogenism, we found that ovarian BMP4 levels were significantly decreased in hyperandrogenism. Elevated androgens inhibited BMP4 expression via activation of androgen receptors. Moreover, BMP4 treatment suppressed androgen synthesis in theca cells and promoted estrogen production in granulosa cells, by regulating the expression of steroidogenic enzymes, including CYP11A, HSD3B2, CYP17A1 and CYP19A1. Consistently, knockdown of BMP4 augmented androgen level and inhibited estrogen level. Mechanistically, Smad signaling rather than the p38 MAPK pathway regulated androgen and estrogen formation, thereby mediating the effect of BMP4. Of note, BMP4-transgenic mice were protected against hyperandrogenism. Our observations clarify a vital role of BMP4 in controlling sex hormone levels, and offer new insights into intervention for managing hyperandrogenism by targeting the BMP4-Smad signaling pathway.//////////////////
Effects of bone morphogenetic protein 4 (BMP4) on in vitro development and survival of bovine preantral follicles enclosed in fragments ovarian tissue. da Cunha EV et al. (2017) The aim of this study was to evaluate the effects of different concentrations of BMP4 on activation, development and mRNA expression of GDF9, BMP15, PCNA, Bax and Bcl2 in cultured bovine follicles enclosed in ovarian tissues. Ovarian tissue fragments were cultured for 6 days in α-MEM+ alone or supplemented with different concentrations of BMP4 (10, 50 or 100 ng/ml). Classical histology was performed to analyze follicle growth and morphology, while real-time PCR was used to analyze mRNA levels in fresh and cultured tissues. After 6 days, the culture of ovarian tissue in α-MEM+ alone or supplemented with 10, 50 or 100 ng/ml BMP4 promoted follicular activation. The different concentrations of BMP4 maintained the percentage of normal follicles similar to results of the control. The presence of 100 ng/ml BMP-4 in culture medium increased oocyte and follicular diameters of primary and secondary follicles when compared with those follicles from uncultured control or cultured in α-MEM+ alone (P < 0.05). The tissues cultured in the presence of increasing concentrations of BMP4 had an increase in mRNA expression of the tested genes, but despite this the differences were not statistically significant. In conclusion, 100 ng/ml BMP4 promotes an increase in diameters of follicles and oocytes of primary and secondary follicles after 6 days of in vitro culture.//////////////////
Effect of bone morphogenetic protein-4 on in vitro growth, steroidogenesis and subsequent developmental competence of the oocyte-granulosa cell complex derived from bovine early antral follicles. Yang Y et al. (2016) Bone morphogenetic proteins (BMPs) play important regulatory roles during folliculogenesis. Theca-derived BMP-4 may be beneficial to in vitro growth culture of early antral follicle-derived oocyte-granulosa cell complexes (OGCs), which is lacking in theca-derived products. BMP-4 (0 control], 10 and 50 ng/mL) was added to growth culture medium. Growth, steroidogenesis and the subsequent developmental competence of OGCs derived from bovine early antral follicles (0.5-1 mm) were examined. At 4, 8 and 12 days of growth culture, progesterone production by granulosa cells was suppressed by the addition of BMP-4 compared to the control (P < 0.05). At 12 days, both the OGC survivability and granulosa cell number in the 50 ng/mL BMP-4 treated group were lower than those of control (48.2 % vs. 67.8 %; 4.96 × 10(4) vs. 8.5 × 10(4) cells; P < 0.05, respectively), while no difference was found between 10 ng/mL and the control. The mean diameters of granulosa cell in the BMP-4 treated groups were smaller than that of the control (P < 0.05). However, the granulosa cell viability, oocyte diameter, oocyte nuclear maturation rate and normal fertilization rate were similar in all of the experimental groups, regardless of the amount of BMP-4 addition (P ˃ 0.05). BMP-4 treated in vitro-grown oocytes showed lower blastocyst rates than untreated ones (P < 0.05). BMP-4 addition during in vitro growth culture suppressed progesterone production and decreased the diameter of granulosa cells, suggesting its effect on steroidogenesis; importantly, it did not affect oocyte growth, nuclear maturation and fertilization. However, BMP-4 impaired subsequent embryonic development, and in higher concentration (50 ng/mL) even compromised OGC viability by suppressing proliferation of granulosa cells.//////////////////
Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling. [Park ES 2013 et al.
OBJECTIVE
To test whether bone morphogenetic protein 4 (BMP4) directly regulates differentiation of adult mouse ovary-derived oogonial stem cells (OSCs) in?vitro.
DESIGN
Animal study.
SETTING
Research laboratory.
ANIMAL(S)
Adult C57BL/6 female mice.
INTERVENTION(S)
After purification from adult ovaries by fluorescence-activated cell sorting, OSCs were cultured without or with BMP4 in the absence or presence of the BMP4 antagonist, Noggin.
MAIN OUTCOME MEASURE(S)
Rates of in?vitro-derived (IVD) oocyte formation and changes in gene expression were assessed.
RESULT(S)
Cultured OSCs expressed BMP receptor (BMPR) 1A (BMPR1A), BMPR1B, and BMPR2, suggesting that BMP signaling can directly affect OSC function. In agreement with this, BMP4 significantly increased the number of IVD oocytes formed by cultured OSCs in a dose-dependent manner, and this response was inhibited in a dose-dependent fashion by cotreatment with Noggin. Exposure of OSCs to BMP4 was associated with rapid phosphorylation of BMPR-regulated Smad1/5/8 proteins, and this response was followed by increased expression of the meiosis initiation factors, stimulated by retinoic acid gene 8 (Stra8), muscle-segment homeobox 1 (Msx1), and Msx2. In keeping with the IVD oocyte formation data, the ability of BMP4 to activate Smad1/5/8 signaling and meiotic gene expression in OSCs was abolished by cotreatment with Noggin.
CONCLUSION(S)
Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in?vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes.
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Effects of BMP4/SMAD signaling pathway on mouse primordial follicle growth and survival via up-regulation of Sohlh2 and c-kit. Ding X et al. Bone morphogenetic protein 4 (BMP4) is essential for the development of primordial follicles, although its underlying mechanism remains largely unknown. By using cultured ovaries, the effects of BMP4 and the potential signal transduction pathways were investigated. Ovaries from 3-day-old female mouse pups were maintained in organ culture in the absence (control) or presence of BMP4 (100 ng/ml). At different culture time, the effects of BMP4 on primordial follicle growth and survival were assayed by follicle count and TUNEL labeling. The expression of phospho-SMAD1/5/8, Sohlh2, and c-kit were measured by immunohistochemistry, RT-PCR, and Western-blotting. Immunohistochemistry was also performed to determine the expression pattern of Bmp4, pSMAD1/5/8, Sohlh2, and c-kit in vivo during ovarian development. The results showed treatments of ovaries with BMP4 resulted in a significant (P<0.05) increase on the primordial-to-primary follicle transition. The oocytes of primordial follicles treated with BMP4 were also less likely to undergo apoptosis. BMP4 enhanced the phosphorylation of SMAD1/5/8 and up-regulated the expression of Sohlh2 and c-kit in primordial follicles. During ovarian development in vivo, Sohlh2 and c-kit exhibited similar expression patterns to BMP4 and pSMAD1/5/8 in primordial follicles. The present studies suggest that BMP4/SMAD signaling pathway initiate primordial follicle growth and prevented oocyte apoptosis via up-regulation of Sohlh2 and c-kit. Mol. Reprod. Dev. ? 2012 Wiley Periodicals, Inc.
BMP4 can generate primordial germ cells from bone marrow-derived pluripotent stem cells. Shirazi R et al. The evidence of germ cell derivation from embryonic and somatic stem cells provides an in vitro model for the study of germ cell development, the associated epigenetic modification and mammalian gametogenesis. More importantly, in vitro derived gametes also represent a potential strategy for treating infertility. In mammals, male and female gametes, oocyte and sperm, are derived from a specific cell population, primordial germ cells (PGCs), that segregate early in embryogenesis. In the present study we tried to isolate pluripotent SSEA-1+ cells from mice bone marrow using MACS system. The SSEA-1+ cells were directly separated from the suspension of murine mononuclear cells (MMCs) harvested from bone marrow of 2-4 weeks old mice. Flowcytometry assay immediately after sorting and culturing under undifferentiated condition showed 55?7% and 87?4% purity, respectively. RT-PCR analysis after differentiation of SSEA-1+ cells into derivations of three germ layers, revealed the pluripotency properties of isolated cells. The SSEA-1+ cells were induced to differentiate along germ cell lineage by adding bone morphogenic factor-4 (BMP4) to medium. The expression of germ cell markers (PGCs, male and female germ cell lineage) was investigated. It is found that adding exogenous BMP4 into culture medium could differentiate pluripotent SSEA-1+ cells isolated from an adult tissue into gametes precursors, primordial germ cells. Differentiated cells expressed specific molecular markers of primordial germ cells including Oct4, fragilis, Stella, and Mvh. Our results showed that BMP4 is not sufficient to induce SSEA-1+ cells-derived PGCs to develop further into late germ cells in vitro.
Bone morphogenetic protein 4 (BMP-4) and BMP-7 induce vascular endothelial growth factor expression in bovine granulosa cells. Shimizu T et al. Bone morphogenetic protein-4 (BMP-4) and BMP-7, theca cell-derived growth factors, directly affect the granulosa cell function. The aim of this study was to examine the involvement of BMP-4 or BMP-7 in vascular endothelial growth factor (VEGF) expression in bovine granulosa cells. Granulosa cells were collected from small follicles (4-6 mm) and seeded at a density of 2-5 ?10(5) cells per well in Dulbecco's modified Eagle's medium (DMEM)/F12 medium with BMP-4 or BMP-7. The expression of VEGF messenger RNA and protein was the maximum when 1.0 ng/mL of BMP-4 was added to the culture medium. On the other hand, 10 ng/mL of BMP-7 significantly increased the expression of the VEGF gene and protein. In addition, BMP-4 stimulated the expression of Smad1 and Smad5 genes in granulosa cells, whereas BMP-7 stimulated the expression of Smad5 gene. These results suggested that BMP-4 and BMP-7 may be associated with VEGF expression via several specific Smads in bovine granulosa cells: BMP-4 via Smad1/Smad5 and BMP-7 via Smad5. In conclusion, theca cell-derived BMP-4 and BMP-7 might contribute to follicular vasculature and development by inducing VEGF expression in granulosa cells.
Bone morphogenetic protein (BMP)-4 and BMP-7 suppress granulosa cell apoptosis via different pathways: BMP-4 via PI3K/PDK-1/Akt and BMP-7 via PI3K/PDK-1/PKC. Shimizu T et al. BMP-4 and BMP-7 are associated with the suppression of granulosa cell apoptosis. LY294002 (PI3K inhibitor) or UCN-01 (PDK-1 inhibitor) increased the percentage of apoptotic cells in the granulosa cells treated with BMP-4 or BMP-7. The inhibitors of ERK and p38 (SB203580) did not increase the percentage of apoptotic cells in the granulosa cells treated with BMP-4 or BMP-7. Akt inhibitor did not induce apoptosis in the BMP-4-treated granulosa cells, whereas it did induce apoptosis of the BMP-7-treated granulosa cells. In the granulosa cells treated with BMP-4, the PKC inhibitor increased the percentage of apoptotic cells. Our data show that BMP-4 and BMP-7 are associated with granulosa cell survival via several non-Smad specific pathways: BMP-4 via the PI3K/PDK-1/PKC and BMP-7 via the PI3K/PDK-1/Akt.
In vivo evidence of role of bone morphogenetic protein-4 in the mouse ovary. Tanwar PS et al. The transition of a primordial follicle to a primary follicle is an early step in folliculogenesis. All female mammals are born with a fixed stock of primordial follicles, and exhaustion of that stock leads to menopause or infertility. Recently, several in vitro studies have indicated that BMP-4, BMP-7, and several other growth factors affect the transition of primordial to primary follicles. The aim of our present study was to investigate role of BMP-4 in this process using passive immunization to investigate the role of BMP-4 in a prepubertal mouse model. After seven days of treatment, the weight of antiBMP-4 treated ovaries was significantly lower than the ovaries from mice treated with nonimmune Ig. The number of primary follicles was lower, and the numbers of primordial follicles were higher in antiBMP-4 treated ovaries compared to control ovaries. Treatment with equine chorionic gonadotrophin (eCG) showed no influence on the effects of antiBMP-4 in the mouse ovary. Thus, the results of our study indicate that in vivo BMP-4 acts as transition factor in transition of primordial to primary follicle.
Fujiwara T, et al 2001 reported that bone morphogenetic protein 4 in the extraembryonic mesoderm
is required for allantois development and the localization and
survival of primordial germ cells in the mouse.
Genetic analysis in the mouse has shown that bone morphogenetic protein 4
(Bmp4) is required for the formation of both PGCs and allantois. Bmp4 is
expressed in both the trophoblast-derived extraembryonic ectoderm (ExE) and in
the epiblast-derived extraembryonic mesoderm (ExM), in which the PGCs,
allantois primordium, and angioblasts are first detected. The authors generated tetraploid (4N) chimeras by aggregating
Bmp4 null ES cells with wild-type tetraploid embryos. In this combination,
wild-type tetraploid cells contribute to the extraembryonic trophoblast and
primitive endoderm lineages but are excluded from the epiblast and its
derivatives, including the ExM. The results clearly demonstrate that Bmp4 made
in the ExM does not affect the establishment of either PGC or allantois lineages,
but is required for PGC localization and survival and for the differentiation of the
allantois. These findings suggest that Bmp4 expressed in epiblast-derived tissues
plays vital roles in reproduction by regulating both the development of the germ
line and the vascular connection between the embryo and the placenta.
Nilsson EE, et al reported that Bone Morphogenetic Protein-4 Acts as an Ovarian Follicle Survival Factor and
Promotes Primordial Follicle Development.
The growth and development of follicles within the ovary are highly dependant upon autocrine and
paracrine signaling involving growth factors from granulosa cells, theca cells, stromal interstitial
cells and the oocytes. The growth factor bone morphogenetic protein-4 (BMP-4) and its receptor
(BMPR-IB) have been detected in ovaries and a mutation in BMPR-IB has been associated with
abnormal ovulation rate. The objective of the current study was to examine the role that BMP-4
plays in the early stages of primordial follicle development. Ovaries from four-day-old rats were
placed into a whole ovary organ culture system for two weeks to investigate the effect that treatment
with exogenous BMP-4 has on early follicle development. BMP-4 treated ovaries had a
significantly higher proportion of developing primary follicles and fewer arrested primordial
follicles than did untreated controls. This indicates that BMP-4 promotes primordial follicle
development and the primordial-to-primary follicle transition. Ovaries were also treated with
neutralizing antibody against BMP-4 to determine effects of removing endogenously produced
BMP-4. Interestingly, ovaries treated with BMP-4 antibody were markedly smaller than controls.
This was associated with a progressive loss of oocytes and primordial follicles, a progressive
increase in cellular apoptosis, and an accompanying loss of normal ovarian tissue morphology over
time. Immunocytochemistry localized BMP-4 protein to isolated stromal cell populations, selected
stromal cells (i.e. pre-theca cells) associated with developing primordial follicles, and the
basement membrane of follicles. Ovaries were treated with BMP-4 and RNA collected after organ
culture to determine whether BMP-4 signaling affects expression of other growth factors. Kit ligand
and basic fibroblast growth factor expression was unchanged, but TGFalpha expression was
decreased in whole ovaries. Taken together these data suggest that BMP-4 plays an important role
in promoting the survival and development of primordial follicles in the neonatal ovary.
Bone Morphogenetic Proteins (BMP) -4, -6, and -7 Potently Suppress Basal and Luteinizing Hormone-Induced Androgen Production by Bovine Theca Interna Cells in Primary Culture: Could Ovarian Hyperandrogenic Dysfunction Be Caused by a Defect in Thecal BMP Signaling?
Glister C, et al
We reported recently that bovine theca interna cells in primary culture express several type-I and type-II receptors for bone morphogenetic proteins (BMPs). The same cells express at least two potential ligands for these receptors (BMP-4 and -7), whereas bovine granulosa cells and oocytes express BMP-6. Therefore, BMPs of intrafollicular origin may exert autocrine/paracrine actions to modulate theca cell function. Here we report that BMP-4, -6, and -7 potently suppress both basal (P < 0.0001; respective IC(50) values, 0.78, 0.30, and 1.50 ng/ml) and LH-induced (P < 0.0001; respective IC(50) values, 5.00, 0.55, and 4.55 ng/ml) androgen production by bovine theca cells while having only a moderate effect on progesterone production and cell number. Semiquantitative RT-PCR showed that all three BMPs markedly reduced steady-state levels of mRNA for P450c17. Levels of mRNA encoding steroidogenic acute regulatory protein, P450scc, and 3beta-hydroxy- steroid dehydrogenase were also reduced but to a much lesser extent. Immunocytochemistry confirmed a marked reduction in cellular content of P450c17 protein after BMP treatment (P < 0.001). Exposure to BMPs led to cellular accumulation of phosphorylated Smad1, but not Smad2, confirming that the receptors signal via a Smad1 pathway. The specificity of the BMP response was further explored by coincubating cells with BMPs and several potential BMP antagonists, chordin, gremlin, and follistatin. Gremlin and chordin were found to be effective antagonists of BMP-4 and -7, respectively, and the observation that both antagonists enhanced (P < 0.01) androgen production in the absence of exogenous BMP suggests an autocrine/paracrine role for theca-derived BMP-4 and -7 in modulating androgen production. Collectively, these data indicate that an intrafollicular BMP signaling pathway contributes to the negative regulation of thecal androgen production and that ovarian hyperandrogenic dysfunction could be a result of a defective autoregulatory pathway involving thecal BMP signaling.
BMP Signalling in the Human Fetal Ovary is Developmentally-regulated and Promotes Primordial Germ Cell Apoptosis. Childs AJ et al. Primordial Germ Cells (PGCs) are the embryonic precursors of gametes in the adult organism, and their development, differentiation and survival is regulated by a combination of growth factors collectively known as the germ cell niche. Although many candidate niche components have been identified through studies on mouse PGCs, the growth factor composition of the human primordial germ cell niche has not been studied extensively. Here we report a detailed analysis of the expression of components of the BMP signalling apparatus in the human fetal ovary, from post-migratory PGC proliferation to the onset of primordial follicle formation. We find developmentally-regulated and reciprocal patterns of expression of BMP2 and BMP4, and identify germ cells to be the exclusive targets of ovarian BMP signalling. By establishing long term cultures of human fetal ovaries in which PGCs are retained within their physiological niche, we find that BMP4 negatively regulates post-migratory PGC numbers in the human fetal ovary by promoting PGC apoptosis. Finally, we report expression of both MSX1 and MSX2 in the human fetal ovary, and reveal a selective up-regulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary, as in other systems. These data reveal for the first time growth factor regulation of human PGC development in a physiologically relevant context, and have significant implications for the development of cultures systems for the in vitro maturation of germ cells, and their derivation from pluripotent stem cells.
Effects of bone morphogenic protein 4 (BMP4) and its inhibitor, Noggin, on in vitro maturation and culture of bovine preimplantation embryos. La Rosa I et al. ABSTRACT: BACKGROUND: BMP4 is a member of the transforming growth factor beta (TGFbeta) superfamily and Noggin is a potent BMP inhibitor that exerts its function by binding to BMPs preventing interactions with its receptors. The aim of this work was to investigate the role of BMP4 and Noggin, on oocytes in vitro maturation (m experiments) and embryos in vitro development (c experiments) of bovine. METHODS: For m experiments, COCs were collected from slaughterhouse ovaries and in vitro matured in TCM with 100 ng/ml of either BMP4 or Noggin. After 24 h, the nuclear stage of the oocytes was determined by staining with Hoechst 33342. In addition, RT- qPCR was performed on MII oocytes to study the relative concentration of ZAR1, GDF9, BAX, MATER and HSP70 transcripts. Treated oocytes were submitted to parthenogenic activation (PA) or in vitro fertilization (IVF) and cultured in CR2. For c experiments, non- treated matured oocytes were submitted to PA or IVF to generate embryos that were exposed to 100 ng/ml of BMP4 or Noggin in CR2 until day nine of culture. Cleavage, blastocyst and hatching rates, expression pattern of the transcription factor Oct-4 in blastocysts and embryo cell number at day two and nine post-activation or fertilization were evaluated. RESULTS: We found that Noggin, as BMP4, did not affect oocyte nuclear maturation.Noggin supplementation up- regulated the expression of HSP70 and MATER genes in matured oocytes. Moreover, BMP4 during maturation increased the proportion of Oct-4 positive cells in parthenogenic embryos. On the other hand, when Noggin was added to embryo culture medium, developmental rates of parthenogenic and in vitro fertilized embryos were reduced. However, BMP4 addition decreases the development only for in vitro fertilized embryos. BMP4 and Noggin during culture reduced the proportion of Oct-4- expressing cells. CONCLUSIONS: Our results show that BMP4 is implicated in bovine oocytes maturation and embryo development. Moreover, our findings demonstrate, for the first time, that a correct balance of BMP signaling is needed for proper pre-implantation development of bovine embryos.
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Mutations |
3 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Lawson KA, et al 1999 reported that Bmp4 is required for the generation of primordial germ cells in
the mouse embryo.
In many organisms the allocation of primordial germ cells (PGCs) is determined
by the inheritance of maternal factors deposited in the egg. However, in mammals,
inductive cell interactions are required around gastrulation to establish the germ
line. The authors show that Bmp4 homozygous null embryos contain no PGCs. They
also lack an allantois, an extraembryonic mesodermal tissue derived, like the
PGCs, from precursors in the proximal epiblast. Heterozygotes have fewer PGCs
than normal, due to a reduction in the size of the founding population and not to an
effect on its subsequent expansion. The initiation of the germ line in the mouse therefore depends on a secreted
signal from the previously segregated, extraembryonic, trophectoderm lineage.
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse Fujiwara T, et al .
Evidence suggests that the specification of primordial germ cells (PGCs) in the mammalian embryo does not depend on maternal determinants. Rather, previous genetic analysis in the mouse has shown that bone morphogenetic protein 4 (Bmp4) is required for the formation of both PGCs and allantois. Bmp4 is expressed in both the trophoblast-derived extraembryonic ectoderm (ExE) and in the epiblast-derived extraembryonic mesoderm (ExM), in which the PGCs, allantois primordium, and angioblasts are first detected. We have shown that Bmp4 made in the ExE functions to induce precursors of PGCs and allantois in the adjacent epiblast, resulting in complete lack of both cell types in homozygous null mutants. However, the function of Bmp4 in the ExM is totally unknown. To address this question, we generated tetraploid (4N) chimeras by aggregating Bmp4 null ES cells with wild-type tetraploid embryos. In this combination, wild-type tetraploid cells contribute to the extraembryonic trophoblast and primitive endoderm lineages but are excluded from the epiblast and its derivatives, including the ExM. Our results clearly demonstrate that Bmp4 made in the ExM does not affect the establishment of either PGC or allantois lineages, but is required for PGC localization and survival and for the differentiation of the allantois. These findings suggest that Bmp4 expressed in epiblast-derived tissues plays vital roles in reproduction by regulating both the development of the germ line and the vascular connection between the embryo and the placenta.
Species: None
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Polymorphism of BMP4 gene in Indian goat breeds differing in prolificacy. Sharma R 2013 et al.
Bone Morphogenetic proteins (BMPs) are members of TGF- (transforming growth factor-beta) superfamily, of which BMP4 is the most important due to crucial role in follicular growth and differentiation, cumulus expansion and ovulation. Reproduction is a crucial trait in goat breeding and based on the important role of BMP4 gene in reproduction it was considered as a possible candidate gene for the prolificacy of goats. The objective of the present study was to detect polymorphism in intronic, exonic and 3?UTR of BMP4 gene in Indian goats. Nine different goat breeds (Barbari, Beetal, Black Bengal, Malabari, Jakhrana (Twinning>40%), Osmanabadi, Sangamneri (Twinning 20-30%), Sirohi and Ganjam (Twinning <10%) differing in prolificacy and geographic distribution were employed for polymorphism scanning. Cattle sequence (AC_000167.1) was used to design primers for amplification of targeted region followed by direct DNA sequencing to identify the genetic variations. Single Nucleotide Polymorphisms (SNPs) were not detected in exon 3, intronic region and the 3?flanking region. A SNP (G1534A) was identified in the exon 2. It's a non-synonymous mutation resulting in Arginine to Lysine change in corresponding protein sequence. G to A transition at 1534 locus revealed two genotypes GG and GA in nine investigated goat breeds. GG genotype was predominant with genotype frequency of 0.98. GA genotype was present in an animal of Black Bengal as well as Jakhrana breed with genotype frequency of 0.02. A microsatellite was identified in the 3' flanking region, only 20 nucleotide downstream from the termination site of coding region, as a short sequence with more than nineteen continuous and repeated CA dinucleotides. Since the gene is highly evolutionary conserved, identification of non-synonymous SNP (G1534A) in coding region gains further importance. To our knowledge, this is the first report of mutation in coding region of caprine BMP4 gene. But whether the reproduction trait of goat is associated with the BMP4 polymorphism, needs to be further defined by association studies in more populations so as to delineate effect on it.
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