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Comment |
Increased bone morphogenetic protein-6 in follicular fluid and granulosa cells may correlate with fertilization and embryo quality in humans. Liang Y et al. (2017) Bone morphogenetic protein-6 (BMP-6), which is a member of the transforming growth factor-β superfamily, is associated with the regulation of bone development and various physiological processes. In the present study, the expression of BMP-6 in follicular fluid and granulosa cells (GCs) from pregnant and non-pregnant patients was explored. A total of 44 pregnant patients (pregnant group) and 36 non-pregnant patients (non-pregnant group) were recruited for the present study. The expression of BMP-6 was detected using western blotting and reverse transcription-quantitative polymerase chain reaction. The expression of BMP-6 was significantly higher at the protein level (P<0.01) in follicular fluid obtained from the pregnant group compared with that from the non-pregnant group. The mRNA and protein expression of BMP-6 in GCs were significantly upregulated in the pregnant group compared with the non-pregnant group (both P<0.01). These results suggest that high expression of BMP-6 in pregnant women may be a novel biomarker for the fertility process.//////////////////
Bone Morphogenetic Protein-6 (BMP-6) Stimulates the Antrum Formation by the Regulation of its Signalling Pathway in Caprine Pre-antral Follicles Cultured In Vitro. Araújo VR et al. (2015) BMP-6 has been found to be important to ovarian cells and oocyte, as well as to uterus. Thus, this study investigated the effect of bone morphogenetic protein (BMP-6) and recombinant follicle-stimulating hormone (rFSH) alone or in combination on the in vitro culture (IVC) of isolated caprine secondary follicles (Experiment 1) and the mRNA levels for BMP receptors/Smad signalling pathway (BMPR1A, BMPR2, SMAD1, SMAD4, SMAD5, SMAD6, SMAD7 and SMAD8) in vivo and in vitro using BMP-6 (Experiment 2). Secondary follicles were cultured in αMEM(+) alone (control medium) or supplemented with BMP-6 at 1 or 10 ng/ml and rFSH alone or the combination of both BMP-6 concentrations and rFSH. The results from Experiment 1 showed that the antrum formation rate was higher in the BMP-6 at 1 ng/ml (p < 0.05) than in MEM. In Experiment 2, the mRNA expression for BMPR2, SMAD1, SMAD5 and SMAD6 was detected in non-cultured control and after in vitro culture (MEM and 1 ng/ml BMP-6); while the expression of SMAD7 and SMAD8 mRNA was only detected after IVC, SMAD4 was only detected in the BMP-6 at 1 ng/ml treatment. In conclusion, the low BMP-6 concentration positively influenced antrum formation and ensured normal mRNA expression for BMP receptor and Smads after IVC of caprine secondary follicles.//////////////////
Effect of BMP-6 on development and maturation of mouse preantral follicles in vitro. Wang X et al. (2015) The aim of this study was to investigate the effect and mechanism of bone morphogenetic protein-6 (BMP-6) on the growth and maturation of mouse follicles in vitro. Preantral follicles isolated from mice were incubated with recombinant human BMP-6 (rhBMP-6) before analysis. BMP-6 expression was detected by immunofluorescence and western blot. Maturation of oocytes was observed microscopically. Estradiol (E2) and progesterone (P4) levels were measured by enzyme-linked immunosorbent assay. Expression of steroidogenesis-related genes was detected by reverse transcription quantitative polymerase chain reaction. There was a marked increase in the preantral follicles maturation in cells incubated with 50 ng/mL of rhBMP-6 for eight days, compared with the control. The levels of E2, P4 and steroidogenesis-related genes were also significantly increased in granulosa cells and theca cells cultured for 6, 10 and 11 days, respectively. Conversely, the preantral follicle maturing rate was remarkably decreased in cells incubated with 50 ng/mL of rhBMP-6 for day 11, accompanied with reduction in E2, P4 levels and steroidogenesis-related genes levels. Meanwhile, compared with the control, the maturing rate was not significantly different in cells incubated with 100 ng/mL of rhBMP-6 for day 8 or day 11. However, the E2 levels and its relevant regulation gene expression all increased significantly, while the P4 content and its relevant regulation gene expression decreased. The results indicate that BMP-6 can promote the maturation of preantral follicles in vitro in a concentration and time-dependent manner and may play a role in the regulation of steroid hormone synthesis and/or secretion.//////////////////
The Role of Bone Morphogenetic Protein 6 in Accumulation and Regulation of Neutrophils in the Human Ovary. Akiyama I 2014 et al.
Bone morphogenetic protein (BMP) cytokine is known to regulate ovulation, as BMP-6 null mice exhibit a decrease in the number of ovulatory follicles without effect on either the morphology or the dynamics of follicular development. In the present study, the role of BMP-6 in ovulatory process was investigated using human granulosa-lutein cells (GCs). Granulosa-lutein cells, obtained from in vitro fertilization patients, were cultured with BMP-6 followed by RNA extraction. The neutrophil-chemotactic activity of the supernatant of cultured GC was investigated. Bone morphogenetic protein 6 significantly increased growth-regulated oncogene a (GRO-a) messenger RNA (mRNA) and protein expression in GC. In the neutrophil-chemotaxis assay, the GC supernatant cultured with BMP-6 attracted more neutrophils than control samples, which was negated with anti-GRO-a neutralizing antibody. Bone morphogenetic protein 6 also suppressed the relative expression of the protease inhibitors, secretory leukocyte peptidase inhibitor, and whey acid protein 14 mRNA in GC. Bone morphogenetic protein 6 might play a role in ovulation by increasing the accumulation of neutrophils in the ovulatory follicle and suppressing the effect of protease inhibitors.
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Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production. Glister C et al. Bone morphogenetic proteins (BMPs) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (-43-fold) with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also down-regulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ~twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling.
Bone morphogenetic protein-6 (BMP-6): mRNA expression and effect on steroidogenesis during in vitro maturation of porcine cumulus oocyte complexes. Ebeling S et al. Oocyte secreted factors (OSFs) have emerged as important factors for follicular development. The present study investigated the effect of the potential OSF bone morphogenic protein (BMP)-6 on steroidogenesis in porcine cumulus oocyte complexes during in vitro maturation. Cumulus oocyte complexes (COCs), cumulus complexes (CCs) without oocytes and CCs with supplemented BMP-6 were cultured for 0, 5, 26 or 46h. BMP-6 transcripts were detected in oocytes and cumulus cells at all time points. In both cell types the mRNA expression was most intense after 5h, and decreased during further maturation. After 26 and 46h of culture, CCs secreted significantly less 17?estradiol than COCs. This effect was reversed by adding BMP-6 to CCs cultures. In addition, a down-regulation of Cyp19A1, the rate-limiting enzyme of 17?estradiol synthesis, was detected in CC cultures after 5h. As seen for 17?estradiol secretion, the addition of BMP-6 caused a significant increase in Cyp19A1 mRNA levels after 5, 26 and 46h of culture. Progesterone secretion and transcripts of steroidogenic marker proteins StAR and 3?HSD were not affected considerably by oocyte removal or addition of BMP-6. Furthermore, BMP-6 did not affect the activity of the mitogen-activated protein kinase. The results indicated that BMP-6 is a potential OSF and is involved in the prevention of premature luteinisation in cumulus cells via enhancing 17?estradiol synthesis. Levels of BMP-6 mRNA in goat ovarian follicles and in vitro effects of BMP-6 on secondary follicle development. Frota IM et al. SummaryExpression of BMP-6 mRNA was quantified by real-time polymerase chain reaction (PCR) and the BMP-6 protein was demonstrated by immunohistochemistry in the primordial, primary, secondary, small and large antral follicles of goat. Furthermore, the influence of BMP-6 on increase in diameter, antrum formation and expression of BMP-6 and FSH-R in in vitro cultured secondary follicles was studied. Therefore, goat primordial, primary and secondary follicles, as well as small and large antral follicles were obtained and the mRNA levels of BMP-6 were quantified by PCR in real time. Expression of BMP-6 protein in goat follicles was demonstrated by immunohistochemistry. The influence of BMP-6 in the presence or absence of follicle-stimulating hormone (FSH) on both the development of secondary follicles and the expression of mRNA for BMP-6 and FSH-R was evaluated after 6 days of culture. Furthermore, the follicular diameter and the formation of the antrum were evaluated before and after 6 days of culture and compared by Kruskal-Wallis and chi-squared tests (P < 0.05), respectively. The results show that the level of mRNA for BMP-6 in primary and secondary follicles was significantly higher than in the primordial follicles (P < 0.05). Similar levels of BMP-6 mRNA were observed in cumulus-oocyte complexes and mural granulosa/theca cells from small and large antral follicles, respectively. BMP-6 protein was expressed in oocytes of all categories of follicles and in granulosa cells from secondary follicles onwards. Addition of BMP-6 to the culture medium increased the diameter of secondary follicles mainly by antrum formation after 6 days' culture, in the presence or absence of FSH (P < 0.05). Furthermore, addition of FSH resulted in increased levels of BMP-6 mRNA in these follicles (P < 0.05). Simultaneous administration of FSH and BMP-6 enhanced the levels of FSH receptor (FSH-R) mRNA (P < 0.05). It is concluded that BMP-6 mRNA is increased during transition from primordial to primary/secondary follicles in the goat ovaries and that BMP-6 enhances the growth of cultured secondary follicles.
Effect of Direct Ovarian Infusion of Bone Morphogenetic Protein 6 (BMP6) on Ovarian Function in Sheep. Campbell BK et al. BMP6 has been suggested as an important local factor capable of modulating the stimulatory actions of FSH in granulosa cells in vitro. The objective of this experiment was to determine the effect of direct ovarian infusion of BMP6 (2 microg/h) on ovarian function in ewes with an autotransplanted ovary. Treated (n = 6) and vehicle treated controls (n = 6) were infused during the early follicular phase, between 12-24 h after luteal regression and ovarian response determined by collection of samples of ovarian venous blood and transdermal ultrasound. In the absence of any change in circulating gonadotropins or in the antral follicle population, BMP6 infusion resulted in acute but transient increases in ovarian inhibin A, androstenedione and estradiol secretion (P < 0.05) during the second half of the infusion period. Thereafter, treated animals had an advance in the time of the LH surge by around 10 h (43.3 +/- 2.8 h in treated vs 53.3 +/- 2.7 h in controls; P < 0.05) and smaller pre-ovulatory follicles (4.1 +/- 0.2 mm in treated vs 5.3 +/- 0.1 mm in controls; P < 0.01) which gave rise to smaller corpora lutea (9.5 +/- 0.8 mm in treated vs 11.7 +/- 0.6 mm in controls; P < 0.05). There was, however, no effect of infusion on ovulation rate and despite these changes in the size of the ovulatory follicle, when the hormonal data was aligned to the time of the LH surge, there were no differences in preovulatory estradiol, androstenedione or inhibin A between groups. This study therefore provides strong in vivo evidence to support the hypothesis that BMP6 is an important local regulator of ovarian function and that alterations in BMP6 cellular signaling may explain some of the effects of the FecB mutation in inducing precocious maturation of ovulatory follicles.
Evidence for an inhibitory role of bone morphogenetic protein(s) in the follicular-luteal transition in cattle. Knight PG et al. Bone morphogenetic proteins (BMPs) and their receptors are expressed in theca and granulosa cells and BMPs have been implicated in the regulation of folliculogenesis. Their potential involvement in luteal function has received less attention. Here, we first compared relative abundance of mRNA transcripts for BMPs, activin-bA and BMP/activin receptors in bovine corpus luteum (CL) and follicular theca and granulosa layers before undertaking functional in-vitro experiments to test effect of selected ligands (BMP-6 and activin-A) on luteinizing bovine theca and granulosa cells. Relative to beta-actin, CL tissue contained more BMP-4 and -6 mRNA than granulosa, more BMP-2 mRNA than theca but much less activin-bA mRNA than both granulosa and theca. Transcripts for all seven BMP/activin receptors were readily detected in each tissue and two transcripts (BMPRII, ActRIIA) were more abundant in CL than either theca or granulosa, consistent with tissue responsiveness. In-vitro luteinization of theca and granulosa cells from antral follicles (4-6mm) was achieved by culturing with 5% serum for 6 days. BMP-6 and activin-A suppressed forskolin-induced progesterone secretion from both cell types without affecting cell number. BMP-6 reduced forskolin-stimulated up-regulation of StAR mRNA and raised basal CYP17 mRNA level in theca-lutein cells without affecting expression of CYP11A1 or 3bHSD. In granulosa-lutein cells, StAR transcript abundance was not affected by BMP-6, whereas forskolin-induced expression of CYP11A1, 3bHSD, CYP19 and oxytocin transcripts was reduced. In both cell types, follistatin attenuated the suppressive effect of activin-A and BMP-6 on forskolin-induced progesterone secretion but had no effect alone abstract truncated 250W].
[Otsuka F,etal reported the biological function and
cellular mechanism of bone morphogenetic protein-6
in the ovary.
BMP-6 is an oocyte-derived member of the transforming growth factor-b superfamily. Unlike BMP-15 and
GDF-9, BMP-6 lacks mitogenic activity on rat granulosa cells (GCs) and produces a marked
decrease in follicle-stimulating hormone (FSH)-induced progesterone production without
affecting estradiol production, demonstrating not only the
first identification of GCs as BMP-6
targets in the ovary but also its selective modulation of
FSH action in steroidogenesis. BMP-6 also exhibited
similar action to BMP-15 by attenuating the steady state
mRNA levels of FSH-induced
steroidogenic acute regulatory protein (StAR) and P450
side-chain cleavage enzyme (P450scc),
without affecting P450 aromatase mRNA level, supporting its
differential function on
FSH-regulated progesterone and estradiol production.
However, unlike BMP-15, BMP-6
inhibited forskolin- but not 8-Br-cAMP-induced progesterone
production, StAR and P450scc
mRNA expression. BMP-6 also decreased FSH- and
forskolin-stimulated cAMP production,
suggesting that the underlying mechanism by which BMP-6
inhibits FSH action most likely
involves the down-regulation of adenylate cyclase activity.
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.Differential regulation of steroidogenesis by bone morphogenetic proteins in granulosa cells: Involvement of ERK signaling and oocyte actions in FSH-induced estrogen production. Miyoshi T et al. In the present study we investigated the cellular mechanism by which oocytes and BMPs govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Since BMP-7 changed neither forskolin- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-PKA pathway. Treatment with FSH, but not cAMP, activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor U0126 increased estradiol production and decreased FSH- and forskolin-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH-induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. On the other hand, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was upregulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH-induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.
Bone morphogenetic protein-6 stimulates gene expression of follicle-stimulating hormone receptor, inhibin/activin beta subunits, and anti-M?an hormone in human granulosa cells. Shi J et al. Immunohistochemical staining using human normal ovaries showed that bone morphogenetic protein-6 (BMP-6) was abundantly present in the granulosa cells (GC) of healthy tertiary follicles but not in atretic follicles. An in vitro study showed that BMP-6 induced gene expression of FSH receptor, inhibin/activin beta subunits, and anti-M?an hormone (AMH) in human GCs, suggesting that BMP-6 is an important mediator to support healthy follicle growth in the human ovary.
Improvement of ovarian response and oocyte quality of aged female by administration of bone morphogenetic protein-6 in a mouse model. Park SS et al. ABSTRACT: BACKGROUND: Advancing female age remains a difficult problem in infertility treatment. Ovarian angiogenesis plays an important role in follicular development and the activation of ovarian angiogenesis has been emerged as a new strategy for the improvement of age-related decline of oocyte quality. BMP-6 affect gonadotropin signals in granulosa cells and it promotes normal fertility by enabling appropriate response to LH and normal oocyte quality. BMP-6 has a potential role in regulation of angiogenesis and regulates the expression of inhibitor of DNA-binding proteins (Ids). Ids involved in the control and timing of follicle selection and granulosa cells differentiation. Especially, Id-1 is well-characterized target of BMP-6 signaling. Therefore, this study investigated whether co-administration of BMP-6 during superovulation process improves ovarian response, oocyte quality and expression of Id-1 and vascular endothelial growth factor (VEGF) in the ovary of aged female using a mouse model. METHODS: Aged C57BL/6 female mice (26--31 weeks old) were superovulated by injection with 0.1 mL of 5 IU equine chorionic gonadotropin (eCG) containing recombinant mouse BMP-6 at various doses (0, 0.01, 0.1, 1, and 10 ng), followed by injection with 5 IU human chorionic gonadotropin (hCG) 48 h later. Then, the mice were immediately paired with an individual male. The aged control group was superovulated without BMP-6. Young mice of 6--9 weeks old were superovulated without BMP-6 as a positive control for superovulation and in vitro culture of embryos. Eighteen hours after hCG injection, zygotes were retrieved and cultured for 4 days. Both ovaries of each mouse were provided in the examination of ovarian expression of Id-1 and VEGF by reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemistry. RESULTS: Administration of 0.1 ng BMP-6 significantly increased the number and blastocyst formation rate of oocytes ovulated and ovarian expression of Id-1 and VEGF compared to aged control mice. These increased levels were comparable to those of young control mice. CONCLUSIONS: This result suggests that BMP-6 during ovulation induction plays an important role in improvement of oocyte quality and ovarian response of aged female, possibly by regulating of ovarian Id-1 and VEGF expression.
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Mutations |
2 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: BMP6 mutant mice are viable and fertile, and show no overt defects in tissues known to express BMP6 mRNA. However, careful examination of skeletogenesis in late gestation embryos reveals a consistent delay in ossification strictly confined to the developing
sternum. Solloway et al. (1998), find that BMP2 and BMP6 are coexpressed in hypertrophic cartilage, suggesting that BMP2 may functionally compensate in BMP6 null mice.
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Does Bone Morphogenetic Protein 6 (BMP6) Affect Female Fertility in the Mouse? Sugiura K et al. Bone morphogenetic protein 6 (BMP6) is a TGFbeta superfamily member produced by mammalian oocytes as well as other cell types. Despite well-characterized effects of recombinant BMP6 on granulosa cells in vitro, BMP6 function in vivo has been ill-defined. Therefore, the effects of genetic deletion of Bmp6 gene on female mouse fertility were assessed. The mean litter size of Bmp6(-/-) females was reduced significantly by 22% (P < 0.05) compared to Bmp6(+/+) controls. Not only did Bmp6(-/-) females naturally ovulate 24% fewer eggs, but competence of in-vitro matured oocytes to complete preimplantation development after fertilization in vitro was decreased by 50%. There was no apparent effect of Bmp6 deletion on either the morphology or dynamics of follicular development. Nevertheless, levels of LH/human chorionic gonadotropin (hCG)-induced transcripts, which encode proteins required for cumulus expansion (HAS2, PTGS2, PTX3, and TNFAIP6), and epidermal growth factor (EGF)-like peptides (AREG, BTC and EREG), were lower in Bmp6(-/-) mice than in controls after administration of a reduced dose of hCG (1 IU) in vivo. LH receptor (Lhcgr) transcript levels were not significantly less in Bmp6(-/-) granulosa cells, suggesting that BMP6 is required for processes downstream of LH receptors. To assess whether another oocyte derived BMP, BMP15, could have BMP6-redundant functions in vivo, the fertility of Bmp15/Bmp6 double mutants was assessed. Fertility was not significantly reduced in double-homozygous mutants when compared with that of double-heterozygous controls. Therefore, BMP6 promotes normal fertility in female mice, at least in part, by enabling appropriate responses to LH and normal oocyte quality. Therefore, Bmp6 is probably a part of the complex genetic network that determines female fertility.
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