Expression and Function of Fibroblast Growth Factor 18 in the Ovarian Follicle in Cattle1

Abstract

Fibroblast growth factors (FGF) are involved in paracrine signaling between cell types in the ovarian follicle. FGF8, for example, is secreted by oocytes and controls cumulus cell metabolism. The closely related FGF18 is also expressed in oocytes in mice. The objective of this study was to assess the potential role of FGF18 in follicle growth in a monovulatory species, the cow. Messenger RNA encoding FGF18 was detected primarily in theca cells, and in contrast to the mouse, FGF18 was not detected in bovine oocytes. Addition of FGF18 protein to granulosa cell cultures inhibited estradiol and progesterone secretion as well as the abundance of mRNA encoding steroidogenic enzymes and the follicle-stimulating hormone receptor. In vivo, onset of atresia of the subordinate follicle was associated with increased thecal FGF18 mRNA levels and FGF18 protein in follicular fluid. In vitro, FGF18 altered cell cycle progression as measured by flow cytometry, resulting in increased numbers of dead cells (sub-G1 peak) and decreased cells in S phase. This was accompanied by decreased levels of mRNA encoding the cell cycle checkpoint regulator GADD45B. Collectively, these data point to a unique role for this FGF in signaling from theca cells to granulosa cells and suggest that FGF18 influences the process of atresia in ovarian follicles.

Mechanisms of fibroblast growth factor signaling in the ovarian follicle

“…Unlike the known actions of other FGFs in the ovary, however, FGF18 appears to be a proapoptotic factor. Abundance of FGF18 mRNA and protein is higher in atretic compared with growing bovine follicles, and addition of FGF18 increased the amount of DNA laddering and caspase-3 activation in granulosa cells in vitro (Portela et al 2010(Portela et al , 2015. The mechanisms of action of FGF18 in the follicle have not been fully elucidated, but it may act through a murine double minute 2 (MDM2) and p53 upregulated modulator of apoptosis (PUMA, also known as BBC3) pathway (Portela et al 2015), although it has not yet been shown whether FGF18 alters p53 signaling.…”

“…Messenger RNA was not readily detected in the oocyte of cattle but is abundant in theca cells (Portela et al 2010). Addition of recombinant FGF18 to bovine granulosa cells in vitro inhibited oestradiol and progesterone secretion, and lowered abundance of mRNA encoding major estrogenic and progestagenic enzymes (Portela et al 2010).…”

“…Consistent with the pattern observed in organogenesis, FGF10 is expressed predominantly in theca (mesenchymal) cells (Buratini et al 2007) and FGFR2b mRNA is detected predominantly in granulosa (epithelial) cells (Berisha et al 2004). Messenger RNA encoding FGF18 is also detected in theca cells (Portela et al 2010) although expression of FGFR2c and FGFR3c is detectable in both granulosa and theca cells (Berisha et al 2004, Buratini et al 2005. This is not inconsistent with the developmental change of expression of FGFR2c in the embryonic mouse, for which mRNA is detected only in the epithelium of very early lung and limb buds (Oldridge et al 1999, Usui et al 2004) and becomes detectable also in the mesenchyme after embryonic day 15 (Usui et al 2004).…”

Effect of the FGF2 SNP11646 on milk production and fertility traits of Holstein cattle

“…FGF2 is a candidate gene for fertility in cattle (Oikonomou et al 2011) and has been implicated in ovarian function (Portela et al 2010), embryonic development (Jackson et al 1997), and mortality (Khatib et al 2010). FGF2 is also known as mitogen, morphogen, and angiogenic factor (Michael et al 2006).…”

Expression and Localization of Fibroblast Growth Factor 10 (FGF10) in Ovarian Follicle During Different Stages Development in Buffalo

“…The FGFs modulates a wide variety of ovarian function including proliferation, differentiation, steroidogenesis and apoptosis of GC in many farm animal species including human suggesting their role in regulation of ovarian folliculogenesis (Lavranos et al, 1994;Vernon and Spicer, 1994;Parrott and Skinner, 1997;Roberts and Ellis, 1999;Berisha et al, 2004;Buratini et al, 2007;Matos et al, 2007;Machado et al, 2009;Portela et al, 2010).…”