Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9

Abstract

Growth differentiation factor-9 (GDF-9) is a glycoprotein secreted by the oocyte that is capable of stimulating granulosa cell proliferation and inhibiting differentiation. GDF-9 is a member of the transforming growth factor beta superfamily of ligands known to signal through type I and II serine/threonine kinase receptors. In the sequenced human genome, seven type I and six type II receptors have been identified. Based on phylogenetic and sequence analyses, we predicted that GDF-9 likely interacts with known type I and type II receptors. We obtained soluble chimeric proteins with the ectodomains of candidate receptors fused to the Fc portion of immunoglobin and tested their ability to act as functional antagonists. Addition of bone morphogenetic protein receptor type II (BMPRII) ectodomain was most effective in blocking GDF-9 stimulation of granulosa cell proliferation and GDF-9 suppression of FSH-stimulated progesterone production. In addition, the ectodomains of bone morphogenetic protein receptor type IA, bone morphogenetic protein receptor type IB, and activin receptor type IIA were partially effective in blocking GDF-9 action. Furthermore, the BMPRII ectodomain directly interacted with GDF-9 in a coprecipitation study demonstrating the role of the BMPRII ectodomain as a binding protein for GDF-9. To demonstrate the role of BMPRII in GDF-9 signaling in follicular cells, the expression of this protein was blocked in cultured granulosa cells using specific BMPRII antisense oligomers. Inhibition of BMPRII biosynthesis completely prevented the GDF-9 induction of granulosa cell thymidine incorporation. GDF-9 expression is essential for early follicle development, and the presence of the type II and type I receptors in the neonatal rat ovary was verified by reverse transcription polymerase chain reaction. These results demonstrate the important role of BMPRII in mediating GDF-9 action in granulosa cells from small antral follicles and indicate that the effects of GDF-9 might be transduced by binding to BMPRII and one or more type I receptors.