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Program for Developmental and Reproductive Biology, Biomedicum Helsinki, and Departments of Bacteriology and Immunology, Haartman Institute (N.K.-O., J.B., M.K., J.K., K.V., J.P.K., O.R.), University of Helsinki, 00014 Helsinki, Finland; Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University (U.V., M.H., A.J.W.H.), Palo Alto, California 94305; School of Biological and Molecular Sciences, Oxford Brookes University (M.C., N.P.G.), Headington, Oxford, United Kingdom OX3 0BP; Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki (V.M.O.), 00251 Helsinki, Finland; Ludwig Institute for Cancer Research, Uppsala Branch (A.M.), SE-752 37 Uppsala, Sweden; and Department of Cellular Biochemistry, Netherlands Cancer Institute (P.t.D.), 1066 CX Amsterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. Olli Ritvos, Biomedicum Helsinki, Room C502b, P.O. Box 63, Haartmaninkatu 8, University of Helsinki, 00014 Helsinki, Finland. E-mail: olli.ritvos{at}helsinki.fi.
The TGFß family member growth differentiation factor-9 (GDF-9) is an oocyte-derived factor that is essential for mammalian ovarian folliculogenesis. GDF-9 mRNAs have been shown to be expressed in the human ovarian follicle from the primary follicle stage onward, and recombinant GDF-9 has been shown to promote human ovarian follicle growth in vitro. In this study with primary cultures of human granulosa-luteal (hGL) cells, we investigated whether recombinant GDF-9 activates components of the Smad signaling pathways known to be differentially activated by TGFß and the bone morphogenetic proteins (BMPs). As with TGFß, GDF-9 treatment caused the phosphorylation of endogenous 53-kDa proteins detected in Western blots with antiphospho-Smad2 antibodies (
PS2). However, unlike BMP-2, GDF-9 did not activate the phosphorylation of antiphospho-Smad1 antibody (PS1)-immunoreactive proteins in hGL cells. Infection of hGL cells with an adenovirus expressing Smad2 (Ad-Smad2) confirmed that GDF-9 activates specifically phosphorylation of the Smad2 protein. Infection of hGL cells with Ad-Smad7, which expresses the inhibitory Smad7 protein, suppressed the levels of both GDF-9-induced endogenous and adenoviral PS2-reactive proteins. Furthermore, GDF-9 increased the steady state levels of inhibin ßB-subunit mRNAs in hGL cells and strongly stimulated the secretion of dimeric inhibin B. Again, Ad-Smad7 blocked GDF-9-stimulated inhibin B production in a concentration-dependent manner. We identify here for the first time distinct molecular components of the GDF-9 signaling pathway in the human ovary. Our data suggest that GDF-9 mediates its effect through the pathway commonly activated by TGFß and activin, but not that activated by many BMPs. The results are also consistent with the suggestion that in addition to endocrine control of inhibin production by gonadotropins, a local paracrine control of inhibin production is likely to occur via oocyte-derived factors in the human ovary.
The work of the Ritvos laboratory was supported by grants from the Academy of Finland, the Finnish National Technology Agency, The Juselius Foundation, The Jalmari and Rauha Ahokas Foundation, the Novo Nordisk Foundation, the Finska Läkaresällskapet, and Helsinki University Central Hospital Funds. The Ritvos and Groome laboratories were also supported by joint grants from the European Commission and The Juselius Foundation. The work of P.t.D. was supported by the Netherlands Institute for Earth and Life Sciences (ALW 809.67.024). The work of A.J.W.H.’s laboratory was supported by NIH Grant HD-31398.
N.K.-o. and J.B. are recipients of Ph.D. fellowships from the Helsinki Biomedical Graduate School.
Abbreviations: ActR-II, Activin receptor type II; ALK, activin receptor-like kinase; BMP-2, bone morphogenetic protein-2; BMPR, bone morphogenetic protein receptor; FCS, fetal calf serum; GDF-9, growth differentiation factor-9; hGL, human granulosa-luteal; MOI, multiplicity of infection; PCOS, polycystic ovary syndrome; PS1, antiphospho-Smad1 antibody; PS2, antiphospho-Smad2 antibody; R-Smad, receptor-regulated Smad protein.
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