A functional bone morphogenetic protein system in the ovary

Published on Jun 22, 1999in Proceedings of the National Academy of Sciences of the United States of America9.412
· DOI :10.1073/PNAS.96.13.7282
Shunichi Shimasaki79
Estimated H-index: 79
(UCSD: University of California, San Diego),
R. J. Zachow1
Estimated H-index: 1
+ 6 AuthorsGregory F. Erickson66
Estimated H-index: 66
Bone morphogenetic proteins (BMPs) comprise a large group of polypeptides in the transforming growth factor β superfamily with essential physiological functions in morphogenesis and organogenesis in both vertebrates and invertebrates. At present, the role of BMPs in the reproductive system of any species is poorly understood. Here, we have established the existence of a functional BMP system in the ovary, replete with ligand, receptor, and novel cellular functions. 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. To explore the paracrine function of this BMP system, we examined the effects of recombinant BMP-4 and -7 on FSH (follicle-stimulating hormone)-induced rat granulosa cytodifferentiation in serum-free medium. Both BMP-4 and -7 regulated FSH action in positive and negative ways. Specifically, physiological concentrations of the BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. These effects were dose- and time-dependent. Furthermore, the BMPs increased granulosa cell sensitivity to FSH. Thus, BMPs have now been identified as molecules that differentially regulate FSH-dependent estradiol and progesterone production in a way that reflects steroidogenesis during the normal estrous cycle. As such, it can be hypothesized that BMPs might be the long-sought “luteinization inhibitor” in Graafian follicles during their growth and development.
📖 Papers frequently viewed together
13 Authors (S. M. Galloway, ..., Olli Ritvos)
879 Citations
423 Citations
6 Authors (J Dong, ..., Martin M. Matzuk)
1,325 Citations
#1Jennifer L. Dube (Genetics Institute, Inc.)H-Index: 3
#2Pei WangH-Index: 23
Last. Martin M. Matzuk (BCM: Baylor College of Medicine)H-Index: 117
view all 6 authors...
We have taken advantage of the sequence relationships among the bone morphogenetic proteins (BMPs) to identify the mouse Bmp15 and human BMP15 genes. The 392-amino acid prepropeptides encoded by these BMP genes exhibit significant homology to each other, although the 70% identity observed between the 125-amino acid mature peptides is considerably lower than that seen in comparisons of other mouse and human orthologs. Both genes share a common structural organization and encode mature peptides th...
423 CitationsSource
#1H. Li (UQ: University of Queensland)H-Index: 16
#2P. M. Bartold (UQ: University of Queensland)H-Index: 63
Last. Michael J. Waters (UQ: University of Queensland)H-Index: 71
view all 6 authors...
GH is known to increase the formation of bone and hard tissues of the tooth (dentine, cementum, and enamel), as do bone morphogenetic proteins. GH receptors are expressed in these tissues and could mediate local growth responses. Here we report that both GH and insulin-like growth factor I (IGF-I) are able to increase expression of bone morphogenetic protein-2 and -4 messenger RNAs 4- to 5-fold in human dental pulp fibroblasts in vitro. Induction was seen at physiological concentrations of hormo...
74 CitationsSource
#1Toshihide KuboH-Index: 2
#2Shunichi ShimasakiH-Index: 79
Last. Gregory F. EricksonH-Index: 66
view all 5 authors...
Inhibin-α subunit (Inh-α) gene expression is important for granulosa cell (GC) differentiation and prevention of ovarian tumorigenesis. Studies on Inh-α regulation have implicated activin and insulin-like growth factor-I (IGF-I) in the mechanisms of expression. Here we present evidence that endogenously produced IGF-I plays an obligatory role in activin-induced Inh-α production. Primary cultures of rat GC were incubated with increasing concentrations of various regulatory molecules, and the leve...
12 CitationsSource
The bone morphogenetic proteins are secreted signalling molecules that belong to the transforming growth factor β family of growth and differentiation factors. Individual bone morphogenetic proteins are prominent at many sites during embryogenesis and are likely to be key regulators of early develop
568 CitationsSource
#1Carl-Henrik Heldin (Ludwig Institute for Cancer Research)H-Index: 152
#2Kohei MiyazonoH-Index: 150
Last. Peter ten Dijke (Ludwig Institute for Cancer Research)H-Index: 112
view all 3 authors...
The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-β (TGF-β) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-β. Inhibitory SMADs have b...
3,346 CitationsSource
#1John J. EppigH-Index: 91
#2Franck ChesnelH-Index: 20
Last. Karen WigglesworthH-Index: 38
view all 7 authors...
Abstract Interaction between oocytes and granulosa cells is complex and involves both gap junctions and paracrine signalling factors. Oocyte development in antral follicles is highly dependent on communication with cumulus cells, a subset of granulosa cells that is intimately associated with oocytes. Cumulus cells express characteristics distinct from the mural granulosa cells of preovulatory follicles. The thesis of this paper is that, without the influence of oocytes, the pathway of granulosa ...
207 Citations
#1Hideyuki Beppu (Japan Society for the Promotion of Science)H-Index: 3
#2Osamu Minowa (Japan Society for the Promotion of Science)H-Index: 33
Last. Masahiro Kawabata (Japan Society for the Promotion of Science)H-Index: 45
view all 4 authors...
The cDNA for the mouse bone morphogenetic protein type II receptor (BMPR-II) was isolated using the human counterpart as a probe and its genomic structure was determined. The cDNA encodes a protein of 1,038 amino acids with a single transmembrane domain, a serine/threonine kinase domain, and a long carboxy-terminal tail. The overall amino acid sequence identity between the mouse and the human BMPR-II is 96.6%. mRNA is widely distributed in various adult tissues. The gene is encoded by 13 exons s...
40 CitationsSource
#1Tohru NatsumeH-Index: 59
#2Shuichiro TomitaH-Index: 6
Last. Naoto Ueno (Hokkaido University)H-Index: 91
view all 6 authors...
Abstract Bone morphogenetic proteins (BMPs) are multifunctional proteins that comprise the largest subfamily of the transforming growth factor-β. These proteins bind to types I and II serine/threonine kinase receptors. Ligand-induced heteromeric dimerization of these receptors is the key event in initiation of biological responses. We report here large-scale expression and purification of extracellular domain of the type I receptor for BMP-2/4, using a silkworm expression system. This soluble fo...
78 CitationsSource
#1Risto Jaatinen (UH: University of Helsinki)H-Index: 9
#2Vicki Rosen (UH: University of Helsinki)H-Index: 1
Last. Olli Ritvos (UH: University of Helsinki)H-Index: 53
view all 4 authors...
Bone morphogenetic proteins (BMP) belong structurally to the transforming growth factor-beta superfamily comprising several growth and differentiation factors such as inhibin, activin, and Mullerian inhibitory factor that regulate ovarian function. We studied here the potential expression of BMP-2, -3, and -4 messenger RNAs (mRNAs) in isolated human granulosa cells obtained at oocyte retrieval for in vitro fertilization. Freshly isolated granulosa cells were found to express BMP-3 (also known as...
28 CitationsSource
Abstract The bone morphogenetic proteins (BMPs) constitute a large family of cytokines related to members of the transforming growth factor-β superfamily. Recent evidence, in particular from gene targeting experiments in the mouse, indicates that BMPs are required for mesoderm formation and for the development and patterning of many different organ systems. Significant progress has also been made in understanding the role of BMPs in gastrulation and neurulation in Xenopus and in identifying gene...
725 CitationsSource
Cited By301
Abstract. Previous studies have shown that BMPR1B promotes follicular development and ovarian granulosa cell proliferation, thereby affecting ovulation in mammals. In this study, the expression and polymorphism of the BMPR1B gene associated with litter size in small-tail Han (STH) sheep were determined. The expression of BMPR1B was detected in 14 tissues of STH sheep during the follicular phase as well as in the hypothalamic–pituitary–gonadal (HPG) axis of monotocous and polytocous STH sheep dur...
#1Dongyong Yang (WHU: Wuhan University)H-Index: 4
#2Xiao Yang (PKU: Peking University)H-Index: 2
Last. Yanxiang Cheng (WHU: Wuhan University)H-Index: 9
view all 7 authors...
Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-β (TGF-β) superfamily. BMP4 is a secreted protein that was originally identified due to its role in bone and cartilage development. Over the past decades, extensive literature has indicated that BMP4 and its receptors are widely expressed in the ovary. Dysregulation of BMP4 expression may play a vital role in follicular development, polycystic ovary syndrome (PCOS), and ovarian cancer. In this review, ...
#1J Nikhil Kumar Tej (NDRI: National Dairy Research Institute)
#2P. Johnson (ICAR: Indian Council of Agricultural Research)H-Index: 1
Last. S. Mondal (ICAR: Indian Council of Agricultural Research)H-Index: 5
view all 7 authors...
The role of copper and selenium on activation of estradiol synthesis pathways viz. PKA/AKT/WNT is not clearly elucidated. On this background we attempt to elcuiated the role of copper and selenium on mRNA expression of genes associated with estradiol synthesis in caprine ovarian granulose cell models. Ovarian granulosa cells from medium (3-5 mm) sized follicles were aspirated and distributed separately to different groups. Group I: control, Group II: cupric chloride (Cu: 0.5 mM), Group III: sodi...
#1Myung Jae Jeon (Wake Forest University)H-Index: 1
#2Young Sik Choi (Wake Forest University)H-Index: 1
Last. John D. Jackson (Wake Forest University)H-Index: 26
view all 5 authors...
Ovaries are the primary physiological source of female sex hormones, which play a crucial role in maintaining ovarian cycle, determining secondary sexual characteristics and preparing the endometrium for implantation. In vitro follicle engineering has been used to investigate follicle development, including ovarian hormone production and gamete maturation. To engineer functional follicles, culture and expansion of the primary ovarian cells are essential. However, the phenotypic and functional ch...
1 CitationsSource
#1Izhar Hyder Qazi (Sichuan Agricultural University)H-Index: 9
#2Yutao Cao (CAU: China Agricultural University)H-Index: 1
Last. Hongbing Han (CAU: China Agricultural University)H-Index: 10
view all 7 authors...
: Female reproductive (ovarian) aging is characterized by a marked decline in quantity and quality of follicles and oocytes, as well as alterations in the surrounding ovarian stroma. In our previous report, we have shown that dietary selenium (Se) insufficiency and supplementation differentially impacted the reproductive efficiency in aging mice; however, the precise understanding of such modulation is still incomplete. In the present study, we sought to determine the impact of low (mildly low l...
2 CitationsSource
#1Zhi-Peng Tai (HAU: Huazhong Agricultural University)
#2Shi-Cheng Ling (HAU: Huazhong Agricultural University)H-Index: 6
Last. Xiao-Ying Tan (HAU: Huazhong Agricultural University)H-Index: 13
view all 4 authors...
Abstract In this study, three members of the Bmp family were cloned and characterized in yellow catfish Pelteobagrus fulvidraco, including Bmp2a, Bmp4 and Bmp9. The predicted amino acid sequences of P. fulvidraco Bmp2a, Bmp4 and Bmp9 showed the characteristic domains of the Bmp family, including an N-terminal signal peptide, Arg-X-X-Arg site, TGF-β family signature and seven conserved cysteines, indicating that function is likely to have been conserved during evolution. mRNAs of the three Bmp ge...
#1Ali Falahati (University of Otago)
#2Yuichi Ozaki (University of Otago)H-Index: 17
Last. P. Mark Lokman (University of Otago)H-Index: 22
view all 6 authors...
In the eel ovary, the expression of growth differentiation factor-9 (Gdf9) appears to be largely confined to the germ cell in early stages of oogenesis. However, both the target tissue and the function of Gdf9 in fish remain unknown. This study aimed to describe the abundance and localization of activin receptor-like kinase-5 (Alk5) and bone morphogenetic protein receptor type II (Bmpr2), which together mediate the Gdf9 signal, in the ovary of a basal teleost, the shortfinned eel, Anguilla austr...
#1M. De los Reyes (University of Chile)H-Index: 8
#2J. Palomino (University of Chile)H-Index: 10
Last. Karla Aspee (University of Chile)H-Index: 2
view all 7 authors...
Abstract Cyclooxygenase2 (COX-2), encoded by the Cox-2 gene within the periovulatory follicles is a critical mediator of oocyte development. Growth differentiation factor 9 (GDF-9) and bone morphogenetic protein 15 (BMP-15) participate in the modulation of certain target genes in the ovary, possibly influencing the Cox-2 gene expression. However, this relationship has not been characterized in canines. This study aimed to examine the possible relationships among BMP-15, GDF-9, progesterone and C...
3 CitationsSource
#1Tao Liu (PKU: Peking University)H-Index: 57
#1Tao Liu (PKU: Peking University)H-Index: 30
Last. Jie Yan (PKU: Peking University)H-Index: 27
view all 5 authors...
Mammalian follicles are composed of oocytes, granulosa cells, and theca cells. Theca cells form in the secondary follicles, maintaining follicular structural integrity and secreting steroid hormones. Two main sources of theca cells exist: Wilms tumor 1 positive (Wt1) cells native to the ovary and Gli1 mesenchymal cells migrated from the mesonephros. Normal folliculogenesis is a process where oocytes, granulosa cells, and theca cells constantly interact with and support each other through autocri...
1 CitationsSource
#1Sheelendra Kumar (IVRI: Indian Veterinary Research Institute)H-Index: 1
#2H. Lakshmi Devi (IVRI: Indian Veterinary Research Institute)H-Index: 2
Last. V.S. Chouhan (IVRI: Indian Veterinary Research Institute)H-Index: 15
view all 9 authors...
Abstract The objective of this study was to document the expression and functional role of BMPs in the placental (caruncle; CAR, cotyledon; COT) during different stages of pregnancy in water buffalo. Samples collected from Early pregnancy 1 (EP1); Early pregnancy 2 (EP2), Mid pregnancy (MP), Late pregnancy (LP) while the third stage of oestrus cycle (NP) was taken as control. Also, the synergistic role of BMP4/BMP7 or combination on mRNA expression of vWF, PCNA, StAR, CYP11A1, 3βHSD, and BAX wer...
2 CitationsSource