Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

Abstract

Similar expression to FGF (SEF or IL17RD), is a tumor suppressor and an inhibitor of growth factors as well as of pro-inflammatory cytokine signaling. In this study, we examined the regulation ofSefexpression by gonadotropins during ovarian folliculogenesis. In sexually immature mice,in situhybridization (ISH) localizedSefgene expression to early developing oocytes and granulosa cells (GC) but not to theca cells.Sefwas also expressed in mouse ovarian endothelial cells, in the fallopian tube epithelium as well as in adipose tissue venules. SEF protein expression, determined by immunohistochemistry (IHC), correlated well withSefmRNA expression in GC, while differential expression was noticed in oocytes. HighSefmRNA but undetectable SEF protein levels were observed in the oocytes of primary/secondary follicles, while an inverse correlation was found in the oocytes of preantral and small antral follicles.SefmRNA expression dropped after pregnant mare's serum gonadotropin (PMSG) administration, peaked at 6–8 h after human chorionic gonadotropin (hCG) treatment, and declined by 12 h after this treatment. ISH and IHC localized the changes to oocytes and mural GC following PMSG treatment, whereasSefexpression increased in mural GC and declined in granulosa–lutein cells upon hCG treatment. The ovarian expression ofSEFwas confirmed using human samples. ISH localizedSEFtranscripts to human GC of antral follicles but not to corpora lutea. Furthermore,SEFmRNA was detected in human GC recovered from preovulatory follicles. These results are the first to demonstrate Sef expression in a healthy ovary during folliculogenesis. Hormonal regulation of its expression suggests that Sef may be an important factor involved in intra-ovarian control mechanisms.