Role of the BMP co-receptor Dragon (RGMb) in ovarian follicle development

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The objective of the proposed research is to determine the role of Dragon, a bone morphogenetic protein (BMP) co-receptor, in follicle development in the ovary. Follicle development requires communication between oocytes and granulosa cells. The cellular and molecular processes involved are poorly understood. BMP ligands and receptors are expressed in various cell types within the ovary, and evidence suggests that BMP signaling is critically involved in follicle development. Dragon (RGMb) is one of the three repulsive guidance molecule (RGM) family members, which also include RGMa and RGMc. We have recently identified the three RGM members to be the first known co-receptors for BMP signaling. We have also shown that RGMa and RGMc facilitate the use of BMP type II receptor ActIIA by BMP2 and BMP4 ligands that otherwise prefer signaling via BMPRII. Interestingly, Dragon is exclusively produced by oocytes within the ovary and ActRIIA is the predominant BMP type II receptor in the oocyte, while BMP2 and BMP4 are expressed in granulosa and theca cells. Importantly, our preliminary results show that Dragon knockout mice exhibited defects in development of secondary follicles into antral follicles in homozygous mice and reduced fertility in heterozygous mice. Our hypothesis is that Dragon enhances utilization of ActRIIA by BMP2 and BMP4 as RGMa and RGMc do, thus sensitizing oocytes to BMP2 and BMP4 stimulation. Specifically, I will 1) determine BMP ligands and BMP receptors used by Dragon to enhance BMP signaling;2) study the role of Dragon in follicle development in vivo. We will use cell lines and primary cells established in our previously published work with RGMa and RGMc, and our Dragon knockout mouse model. Information derived from this proposal will shed light on the roles of Dragon in modulating BMP signaling in follicle development. PUBLIC HEALTH RELEVANCE: Ovarian follicle development requires bidirectional communication between oocytes and surrounding granulosa cells. Currently, the molecular mechanisms of this communication are poorly understood. Emerging evidence suggests that the bone morphogenetic protein (BMP) system plays a critical role in this process. The work described here is aimed at proving that a protein called Dragon (also known as repulsive guidance molecule b, RGMb), a newly identified BMP co-receptor, regulates BMP signaling in oocytes by enhancing the utilization of BMP type II receptor ActRIIA by BMP2 and BMP4. This work, therefore, sets out to understand the mechanisms underlying the follicle development that is necessary for normal reproduction. We hope to identify new protein targets for development of methods to better manage fertility and ovarian-based disorders.