A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis.
Although the existence of a regulatory paracrine feedback system between oocytes and follicular somatic cells has been postulated for some time, there has not yet been any definitive evidence that such a communication system exists. Herein we present a previously undescribed oocyte-granulosa cell (GC) feedback communication system involving an oocyte-derived factor, bone morphogenetic protein-15 (BMP-15) and a GC-derived factor, kit ligand (KL), both of which have been shown to be crucial regulators of female reproduction. We used a coculture system of rat oocytes and GCs and found that BMP-15 stimulates KL expression in GCs, whereas KL inhibits BMP-15 expression in oocytes, thus forming a negative feedback loop. Moreover, KL, like BMP-15, exhibited mitotic activity on GCs in the presence of oocytes. Because c-kit (KL receptor) is expressed in oocytes but not GCs, the oocytes must be involved in mediating the KL-induced GC mitosis. Furthermore, the blockage of c-kit signaling in oocytes by using a c-kit neutralizing antibody markedly suppressed BMP-15-induced GC mitosis, suggesting that the oocyte must play a role in the GC responses to BMP-15. In contrast, the c-kit antibody had no effect on the mitotic activities of two other known GC mitogens, activin-A and BMP-7. Altogether, this study presents direct evidence of a negative feedback system governed by oocyte-derived BMP-15 and GC-derived KL, and demonstrates that the mitotic activities of BMP-15 and KL for GCs depend on this oocyte-GC communication system. We hypothesize that the negative feedback system most likely plays a pivotal role in early folliculogenesis.
Otsuka
Fumio
F
Department of Reproductive Medicine, School of Medicine, University of California at San Diego, La Jolla, CA 92093-0633, USA.
Shimasaki
Shunichi
S
D000818:Animals; D055430:Bone Morphogenetic Protein 15; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D004054:Diethylstilbestrol / Q000494:pharmacology; D005246:Feedback; D005260:Female; D006107:Granulosa Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D055429:Growth Differentiation Factor 9; D006133:Growth Substances / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000235:genetics / Q000502:physiology*
C525904:Bmp15 protein, rat; D055430:Bone Morphogenetic Protein 15; D019485:Bone Morphogenetic Proteins; C525899:Gdf9 protein, rat; D055429:Growth Differentiation Factor 9; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019089:Stem Cell Factor; D004054:Diethylstilbestrol