Follistatin inhibits the function of the oocyte-derived factor BMP-15.
Recent studies have highlighted the importance of a novel oocyte-derived growth factor, bone morphogenetic protein-15 (BMP-15) in the regulation of proliferation and differentiation of granulosa cells in the ovary. Namely, BMP-15 stimulates granulosa cell mitosis and inhibits follicle-stimulating hormone (FSH) receptor mRNA expression in granulosa cell, thereby playing a critical role in the elaborate mechanism controlling ovarian folliculogenesis. At present, however, nothing is known about molecules which may regulate the biological activity of BMP-15. Here we demonstrate evidence that follistatin can form an inactive complex with BMP-15, through which follistatin inhibits BMP-15 bioactivities. The binding of follistatin to BMP-15 was directly demonstrated by a surface plasmon resonance biosensor, and the ability of follistatin to inhibit BMP-15 functions was determined by established BMP-15 bioassays using primary rat granulosa cells. Specifically, follistatin attenuated BMP-15 stimulation of granulosa cell proliferation and reversed BMP-15 inhibition of FSH receptor mRNA expression leading to the suppression of FSH-induced progesterone synthesis. This is the first demonstration of the biochemical interaction and biological antagonism of follistatin and BMP-15, which may be involved in the complex yet well-controlled mechanism of the regulation of follicle growth and development.
Otsuka
F
F
Department of Reproductive Medicine, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0633, USA.
Moore
R K
RK
Iemura
S
S
Ueno
N
N
Shimasaki
S
S
D028341:Activins / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D055430:Bone Morphogenetic Protein 15; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D038681:Follistatin; D015870:Gene Expression / Q000187:drug effects; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D055429:Growth Differentiation Factor 9; D006133:Growth Substances / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D009865:Oocytes / Q000187:drug effects* / Q000502:physiology*; D006080:Ovarian Follicle / Q000502:physiology; D011374:Progesterone / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011962:Receptors, FSH / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology
C525904:Bmp15 protein, rat; D055430:Bone Morphogenetic Protein 15; D038681:Follistatin; C525899:Gdf9 protein, rat; D055429:Growth Differentiation Factor 9; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011962:Receptors, FSH; D011994:Recombinant Proteins; D028341:Activins; D011374:Progesterone