scholarly journals Essential role of Bone morphogenetic protein 15 in porcine ovarian and follicular development and ovulation

2019 ◽  
Author(s):  
Yufeng Qin ◽  
Tao Tang ◽  
Wei Li ◽  
Zhiguo Liu ◽  
Xiaoliang Yang ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Essential Role ◽  
Mammalian Species ◽  
Critical Role ◽  
Follicular Development ◽  
Female Fertility ◽  
Regulatory Function ◽  
Morphogenetic Protein ◽  
Bone Morphogenetic Protein 15

ABSTRACTBone morphogenetic protein 15 (BMP15) is a multifunctional oocyte-specific secreted factor. It controls female fertility and follicular development in both species-specific and dosage-sensitive manners. Previous studies found that BMP15 played a critical role on follicular development and ovulation rate of mono-ovulatory mammalian species, but has minimal impact on poly-ovulatory mice. However, whether this is true in non-rodent poly-ovulatory species need to be validated. To investigate this question, we generated a BMP15 knockdown pig model. We found that BMP15 knockdown gilts showed markedly reduced fertility accompanied with phenotype of dysplastic ovaries containing significantly declined number of follicles, increased number of abnormal follicles, and abnormally enlarged antral follicles resulting in disordered ovulation. Molecular and transcriptome analysis revealed that knockdown of BMP15 significantly suppressed cell proliferation, differentiation, Fshr expression, leading to premature luteinization and reduced estradiol production in GCs, and simultaneously decreased the quality and meiotic maturation of oocyte. Our results provide in vivo evidences for the essential role of BMP15 in porcine ovarian and follicular development, and new insight into the complicated regulatory function of BMP15 in female fertility of poly-ovulatory species.

Efficient generation of bone morphogenetic protein 15-edited Yorkshire pigs using CRISPR/Cas9†

2020 ◽  
Vol 103 (5) ◽  
pp. 1054-1068
Author(s):  
Xuan Shi ◽  
Tao Tang ◽  
Qiyuan Lin ◽  
Hongbo Liu ◽  
Yufeng Qin ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Follicular Development ◽  
Female Fertility ◽  
Efficient Generation ◽  
Morphogenetic Protein ◽  
Yorkshire Pigs ◽  
Bone Morphogenetic Protein 15 ◽  
Ovarian Follicular Development

Abstract Bone morphogenetic protein 15 (BMP15), a member of the transforming growth factor beta superfamily, plays an essential role in ovarian follicular development in mono-ovulatory mammalian species. Studies using a biallelic knockout mouse model revealed that BMP15 potentially has just a minimal impact on female fertility and ovarian follicular development in polyovulatory species. In contrast, our previous study demonstrated that in vivo knockdown of BMP15 significantly affected porcine female fertility, as evidenced by the dysplastic ovaries containing significantly decreased numbers of follicles and an increased number of abnormal follicles. This finding implied that BMP15 plays an important role in the regulation of female fertility and ovarian follicular development in polyovulatory species. To further investigate the regulatory role of BMP15 in porcine ovarian and follicular development, here, we describe the efficient generation of BMP15-edited Yorkshire pigs using CRISPR/Cas9. Using artificial insemination experiments, we found that the biallelically edited gilts were all infertile, regardless of different genotypes. One monoallelically edited gilt #4 (Δ66 bp/WT) was fertile and could deliver offspring with a litter size comparable to that of wild-type gilts. Further analysis established that the infertility of biallelically edited gilts was caused by the arrest of follicular development at preantral stages, with formation of numerous structurally abnormal follicles, resulting in streaky ovaries and the absence of obvious estrous cycles. Our results strongly suggest that the role of BMP15 in nonrodent polyovulatory species may be as important as that in mono-ovulatory species.

scholarly journals The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders

2014 ◽  
Vol 20 (6) ◽  
pp. 869-883 ◽  
Author(s):  
Luca Persani ◽  
Raffaella Rossetti ◽  
Elisa Di Pasquale ◽  
Chiara Cacciatore ◽  
Stéphane Fabre
Keyword(s):  
Bone Morphogenetic Protein ◽  
Ovarian Function ◽  
Female Fertility ◽  
Morphogenetic Protein ◽  
Fertility Disorders ◽  
Bone Morphogenetic Protein 15

Effects of bone morphogenetic protein 15 (BMP15) knockdown on porcine testis morphology and spermatogenesis

2020 ◽  
Vol 32 (11) ◽  
pp. 999
Author(s):  
Tao Tang ◽  
Qiyuan Lin ◽  
Yufeng Qin ◽  
Xinyu Liang ◽  
Yang Guo ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Biological Function ◽  
Transforming Growth Factor Β ◽  
Reproductive Capacity ◽  
Ovary Development ◽  
Sperm Viability ◽  
Morphogenetic Protein ◽  
Bone Morphogenetic Protein 15

Bone morphogenetic protein 15 (BMP15) is a member of the transforming growth factor-β (TGFB) superfamily that plays an essential role in mammalian ovary development, oocyte maturation and litter size. However, little is known regarding the expression pattern and biological function of BMP15 in male gonads. In this study we established, for the first time, a transgenic pig model with BMP15 constitutively knocked down by short hairpin (sh) RNA. The transgenic boars were fertile, but sperm viability was decreased. Further analysis of the TGFB/SMAD pathway and markers of reproductive capacity, namely androgen receptor and protamine 2, failed to identify any differentially expressed genes. These results indicate that, in the pig, the biological function of BMP15 in the development of male gonads is not as crucial as in ovary development. However, the role of BMP15 in sperm viability requires further investigation. This study provides new insights into the role of BMP15 in male pig reproduction.

scholarly journals A Covalently Dimerized Recombinant Human Bone Morphogenetic Protein-15 Variant Identifies Bone Morphogenetic Protein Receptor Type 1B as a Key Cell Surface Receptor on Ovarian Granulosa Cells

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1509-1518 ◽  
Author(s):  
Minna M. Pulkki ◽  
David G. Mottershead ◽  
Arja H. Pasternack ◽  
Pranuthi Muggalla ◽  
Helen Ludlow ◽  
...  
Keyword(s):  
Cell Surface ◽  
Bone Morphogenetic Protein ◽  
Granulosa Cells ◽  
Female Fertility ◽  
Inhibin B ◽  
Cell Surface Receptor ◽  
Morphogenetic Protein ◽  
Surface Receptor ◽  
Covalent Dimer ◽  
Bone Morphogenetic Protein 15

Genetic studies have identified bone morphogenetic protein-15 (BMP15) as an essential regulator of female fertility in humans and in sheep. Oocyte-derived BMP15 is a noncovalently linked dimeric growth factor mediating its effects to ovarian somatic cells in a paracrine manner. Although receptor ectodomains capable of binding BMP15 have previously been reported, no cell surface receptor complex involved in BMP15 signaling has previously been characterized. Here we have expressed and purified recombinant human BMP15 noncovalent and covalent dimer variants. The biological effects of these BMP15 variants were assessed in cultured human granulosa-luteal cells or COV434 granulosa cell tumor cells using BMP-responsive transcriptional reporter assays and an inhibin B ELISA. Biochemical characterization of ligand-receptor interactions was performed with affinity-labeling experiments using [125I]iodinated BMP15 variants. Both ligand variants were shown to form homodimers and to stimulate Smad1/5/8 signaling and inhibin B production in human granulosa cells in a similar manner. [125I]Iodination of both ligands was achieved, but only the covalent dimer variant retained receptor binding capacity. The [125I]BMP15S356C variant bound preferentially to endogenous BMP receptor 1B (BMPR1B) and BMPR2 receptors on COV434 cells. Binding experiments in COS cells with overexpression of these receptors confirmed that the [125I]BMP15S356C variant binds to BMPR1B and BMPR2 forming the BMP15 signaling complex. The results provide the first direct evidence in any species on the identification of specific cell surface receptors for a member of the GDF9/BMP15 subfamily of oocyte growth factors. The fact that BMP15 uses preferentially BMPR1B as its type I receptor suggests an important role for the BMPR1B receptor in human female fertility. The result is well in line with the demonstration of ovarian failure in a recently reported human subject with a homozygous BMPR1B loss-of-function mutant.

scholarly journals Effects of active immunization against growth differentiation factor 9 and/or bone morphogenetic protein 15 on ovarian function in cattle

Reproduction ◽  
2009 ◽  
Vol 138 (1) ◽  
pp. 107-114 ◽  
Author(s):  
Jennifer L Juengel ◽  
Norma L Hudson ◽  
Martin Berg ◽  
Keith Hamel ◽  
Peter Smith ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Ovarian Function ◽  
Follicular Development ◽  
Active Immunization ◽  
Ovulation Rate ◽  
Differentiation Factor ◽  
Morphogenetic Protein ◽  
Growth Differentiation Factor 9 ◽  
Bone Morphogenetic Protein 15 ◽  
Ovarian Follicular Development

Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are essential for ovarian follicular growth in sheep, whereas only GDF9 is essential in mice suggesting that the roles of these oocyte-derived growth factors differ among species. At present, however, there is only limited information on the action of BMP15 and GDF9 in other species. Thus, the aim of this experiment was to determine the effect of neutralizing GDF9 and/or BMP15in vivoon ovarian follicular development and ovulation rate in cattle through active immunization using the mature regions of the proteins or peptides from the N-terminal area of mature regions. Immunization with the BMP15 peptide, with or without GDF9 peptide, significantly altered (increased or decreased) ovulation rate. In some animals, there were no functional corpora lutea (CL), whereas in others up to four CL were observed. From morphometric examination of the ovaries, immunization with GDF9 and/or BMP15 reduced the level of ovarian follicular development as assessed by a reduced proportion of the ovarian section occupied by antral follicles. In addition, immunization against GDF9 and/or BMP15 peptides reduced follicular size to <25% of that in the controls. In conclusion, immunization against GDF9 and BMP15, alone or together, altered follicular development and ovulation rate in cattle. Thus, as has been observed in sheep, both GDF9 and BMP15 appear to be key regulators of normal follicular development and ovulation rate in cattle.

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