A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis

Laitinen, Mika; Vuojolainen, Kaisa; Jaatinen, Risto; Ketola, Ilkka; Aaltonen, Jaakko; Lehtonen, Eero; Heikinheimo, Markku; Ritvos, Olli

doi:10.1016/s0925-4773(98)00161-0

Cited by 205 publications

(128 citation statements)

References 17 publications

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“…Hybridization with the sense BMP-15 probe showed only a low level of nonspecific background signal (data not shown). These results are in agreement with previous reports (6,7).…”

Section: Resultssupporting

confidence: 94%

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Bone Morphogenetic Protein-15

Otsuka

Yao

Lee

et al. 2000

Journal of Biological Chemistry

371

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In developing ovarian follicles, the regulation of cell proliferation and differentiation is tightly coordinated. Precisely how this coordination is achieved is unknown, but recent observations have suggested that molecules emitted by the oocyte are involved in the process. The newly discovered oocyte-specific growth factor, bone morphogenetic protein-15 (BMP-15), is one such molecule. At present, nothing is known about the target cells and biological functions of BMP-15. To fill this gap in our knowledge, recombinant BMP-15 and its antibody were produced and used to determine BMP-15 expression and bioactivity. BMP-15 mRNA and protein were shown to be co-expressed in oocytes throughout folliculogenesis, supporting the idea that BMP-15 is a physiological regulator of follicle cell proliferation and/or differentiation. To test this, we used primary cultures of rat granulosa cells (GCs). We found that BMP-15 is a potent stimulator of GC proliferation, and importantly, the mitogenic effect was follicle-stimulating hormone (FSH)-independent. By contrast, BMP-15 alone had no effect on steroidogenesis. However, it produced a marked decrease in FSH-induced progesterone production, but had no effect on FSH-stimulated estradiol production. This result indicates that BMP-15 is a selective modulator of FSH action. In summary, this study identifies GCs as the first target cells for BMP-15. Moreover, it identifies the stimulation of GC proliferation and the differential regulation of two crucial steroid hormones as the first biological functions of BMP-15. Significantly, BMP-15 is the first growth factor that can coordinate GC proliferation and differentiation in a way that reflects normal physiology.

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“…Hybridization with the sense BMP-15 probe showed only a low level of nonspecific background signal (data not shown). These results are in agreement with previous reports (6,7).…”

Section: Resultssupporting

confidence: 94%

“…This factor, which is a new member of the transforming growth factor-␤ (TGF-␤) superfamily, was named bone morphogenetic protein-15 (BMP-15) (6) or GDF-9B (7,8). The primary structure of mouse (6), human (6), and rat (9) BMP-15 most closely resembles that of GDF-9 (6,9).…”

mentioning

confidence: 99%

Bone Morphogenetic Protein-15

Otsuka

Yao

Lee

et al. 2000

Journal of Biological Chemistry

371

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“…To determine whether BMP-15 and GDF-9 can form homodimers we subjected the CM to chemical cross-linking using BS 3 followed by SDS/PAGE immunoblotting analysis (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…Two structurally similar and oocyte-derived growth factors termed growth and differentiation factor-9 (GDF-9) 1 (1, 2) and bone morphogenetic protein-15 (BMP-15, also called GDF-9B) (3,4) have recently been identified by adapting a homologybased PCR cloning and in silico (data base search) cloning strategies using conserved amino acid sequences of BMP subfamily members of the transforming growth factor-␤ (TGF-␤) superfamily. Like other members of the TGF-␤ superfamily, GDF-9 and BMP-15 are synthesized as preproproteins comprised of a signal peptide, a prodomain and a mature (fully processed bioactive)-domain (1,3,4).…”

mentioning

confidence: 99%

“…Like other members of the TGF-␤ superfamily, GDF-9 and BMP-15 are synthesized as preproproteins comprised of a signal peptide, a prodomain and a mature (fully processed bioactive)-domain (1,3,4). Members of the TGF-␤ superfamily possess a proteolytic cleavage site(s) between the pro and mature domain where a specific protease binds and separates these two domains as an important component of the post-translational processing of these molecules (5).…”

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confidence: 99%

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Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

Moore²,

Otsuka³

et al. 2003

Journal of Biological Chemistry

144

138

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Bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9 (GDF-9) are members of the transforming growth factor-␤ superfamily. Both molecules are closely related in their primary structures and share a nearly identical spatiotemporal expression pattern in the oocyte during folliculogenesis in mammals. Here we have established a series of cell lines, which express recombinant BMP-15, GDF-9, or both, and investigated whether they form homodimers and/or heterodimers. We demonstrate the first evidence that both BMP-15 and GDF-9 can form non-covalent homodimers when expressed individually, while when both are coexpressed BMP-15/GDF-9 heterodimers are produced. Interestingly, when GDF-9 and BMP-15 are co-expressed the processing of both proproteins are significantly impaired as compared with that of the singly expressed proproteins, suggesting that the proprotein heterodimer is less susceptible to proteolytic cleavage than the individual homodimers. Since BMP-15 mutant sheep, called Inverdale, exhibit severe defects in ovarian function we have also established stable transformants expressing the mutant BMP-15 (InvBMP-15) alone or together with GDF-9. Although InvBMP-15 was previously predicted to be unable to form homodimers, we show here that it does form non-covalent dimers; however, the processing efficiency of InvBMP-15 proprotein is significantly lower than wild-type BMP-15. Surprisingly, when GDF-9 is co-expressed, the processing and secretion of InvBMP-15 is abolished, and the processing of GDF-9 is also severely impaired, suggesting that the heterodimers of InvBMP-15/GDF-9 proproteins are not susceptible to proteolytic cleavage and thus degrade in the cells. Based on these findings we propose a novel hypothesis that a decrease in GDF-9 secretion may be involved in causing infertility in homozygous Inverdale ewes.

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