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(777) INTERMEDIN IS A CUMULUS OOCYTE COMPLEX SURVIVAL FACTOR ACTING THROUGH THE CRLR/RAMP RECEPTORS. Chang, Chia Lin1, Roh, Jaesook1, Hsu, Sheau Yu1, 1 Stanford University, Stanford, CA ABSTRACT- Calcitonin gene related peptides (CGRPs) and adrenomedullin (ADM) are tissue-specific peptide hormones important for neurotransmission and cardiovascular homeostasis. These ligands signal through receptor complexes containing the calcitonin receptor-like receptor (CRLR) and one of the three receptor activity-modifying proteins (RAMPs). Based on comparative sequence analysis, we identified intermedin as a novel calcitonin/CGRP family peptide and demonstrated that intermedin signals through the CRLR/RAMP receptor complexes (Roh et al., 2004. JBC 279:7264-74). Analysis of the intermedin expression profile showed that intermedin transcript is expressed in female germ cells of mammals whereas transcripts encoding intermedin receptor complexes are expressed in ovarian granulosa cells, suggesting that intermedin signaling may play an important role in the regulation of ovarian function. Studies using cultured granulosa cells from DES-implanted immature rats demonstrated that intermedin treatment leads to an increase of cAMP production, estradiol synthesis, and thymidine incorporation in granulosa cells. Thus, it is possible that the CRLR/RAMP signaling participates in the maintenance of follicle survival with other ovarian survival factors during follicle development. Of importance, treatment of cumulus oocyte complexes with intermedin or the related peptides, CGRP or ADM, showed that the activation of CRLR/RAMP signaling inhibits cumulus cell death induced by serum deprivation, and maintains the coherence of cumulus oocyte complexes under serum-free conditions. In contrast, treatment with an anti-intermedin antibody leads to disintegration of the cumulus oocyte complexes in the presence of follicle stimulating hormone. Because intermedin is expressed by oocytes, coordination of intermedin expression and CRLR/RAMP receptor signaling in neighboring cumulus cells may be critical for the survival and maintenance of cumulus oocyte complexes as a follicle expands during folliculogenesis. The identification of intermedin as a novel oocyte-derived peptide ligand playing critical roles in the maintenance of the cumulus oocyte complex provides insight and a novel agent with which to further understanding female germ cell development during folliculogenesis. KEY WORDS: follicle, granulosa, intermedin, FSH |
