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 of Sef expression by gonadotropins during ovarian folliculogenesis. In sexually immature mice, in situ hybridization (ISH) localized Sef gene expression to early developing oocytes and granulosa cells (GC) but not to theca cells. Sef was 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 with Sef mRNA expression in GC, while differential expression was noticed in oocytes. High Sef mRNA 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. Sef mRNA 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, whereas Sef expression increased in mural GC and declined in granulosa-lutein cells upon hCG treatment. The ovarian expression of SEF was confirmed using human samples. ISH localized SEF transcripts to human GC of antral follicles but not to corpora lutea. Furthermore, SEF mRNA 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.

Transcriptome analyses of ovarian stroma: tunica albuginea, interstitium and theca interna

“…Mutation of the ACD gene results in reduced follicular development and fertility (Keegan et al 2005). Similar expression to FGF (SEF or IL17RD) has been localised to the membrana granulosa and theca interna of preovulatory human ovaries (Lutwak et al 2014). IL17RD inhibits FGF signalling (Tsang et al 2002), and it is downregulated in cancerous tissues.…”

Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling

“…It is possible that IL17RD might affect initial Gonadotrophin Releasing Hormone (GnRH) secretory neuron specification and homeostatic capacity in the hypothalamus by virtue of its known function as a suppressor of neuronal differentiation, or that of those of its effector gonadotropic neurons in the pituitary [19,31,58]. IL17RD might also function downstream of gonadotropins to regulate the responsiveness of gonadal tissue and other affected neuronal networks (olfactory and auditory), given that IL17RD is expressed in olfactory placodes in mice [11,58]; and dysregulation of IL17RD expression is known to affect the functioning of auditory circuits in zebrafish, chick and mice [12,19,28,31,58,62,63]. Alternately, given its oligogenic mode of interaction in the context of these diseases, it is possible that IL17RD might epistatically regulate the expression of another gene that might affect any of these functions.…”