Actions of Epidermal Growth Factor Receptor/Mitogen-Activated Protein Kinase and Protein Kinase C Signaling in Granulosa Cells from Gallus gallus Are Dependent upon Stage of Differentiation1

Abstract

Studies in both mammalian and nonmammalian ovarian model systems have demonstrated that activation of the mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways modulates steroid biosynthesis during follicle development, yet the collective evidence for facilitory versus inhibitory roles of these pathways is inconsistent. The present studies in the hen ovary describe the changing role of MAPK and PKC signaling in the regulation of steroidogenic acute regulatory protein (STAR) expression and progesterone production in undifferentiated granulosa cells collected from prehierarchal follicles prior to follicle selection versus differentiated granulosa from preovulatory follicles subsequent to selection. Treatment of undifferentiated granulosa cells with a selective epidermal growth factor receptor (EGFR) and ERBB4 receptor tyrosine kinase inhibitor (AG1478) both augments FSH receptor (Fshr) mRNA expression and initiates progesterone production. Conversely, selective inhibitors of both EGFR/ERBB4 and MAPK activity attenuate steroidogenesis in differentiated granulosa cells subsequent to follicle selection. In addition, inhibition of PKC signaling with GF109203X augments FSH-induced Fshr mRNA plus STAR protein expression and initiates progesterone synthesis in undifferentiated granulosa cells, but inhibits both gonadotropin-induced STAR expression and progesterone production in differentiated granulosa. Granulosa cells from the most recently selected (9- to 12-mm) follicle represent a stage of transition as inhibition of MAPK signaling promotes, while inhibition of PKC signaling blocks gonadotropin-induced progesterone production. Collectively, these data describe stage-of-development-related changes in cell signaling whereby the differentiation-inhibiting actions of MAPK and PKC signaling in prehierarchal follicle granulosa cells undergo a transition at the time of follicle selection to become obligatory for gonadotropin-stimulated progesterone production in differentiated granulosa from preovulatory follicles.

Bone Morphogenetic Protein 4 Supports the Initial Differentiation of Hen (Gallus gallus) Granulosa Cells

“…There is also much evidence that cell signaling via the mitogen-activated protein kinase (MAPK) pathway maintains the granulosa layer from prehierarchal follicles in an undifferentiated state [17,18]. In this regard, BMP2 was found to suppress TGFb1-induced FSHR expression, and this inhibitory effect was attributed to enhanced epidermal growth factor receptor ligand (EGFRL) expression and inhibitory MAPK signaling [19].…”

Epidermal growth factor differentially regulates activin subunits in the zebrafish ovarian follicle cells via diverse signaling pathways

“…Inhibition of MAPK3/1 signaling partially abolished EGF-or LH-induced oocyte maturation (Reizel et al, 2010;Hsieh et al, 2011) but completely suppressed FSH-induced oocyte maturation in cumulus-oocyte complex (Su et al, 2002). In addition to regulating oocyte maturation, EGF-induced MAPK3/1 signaling also regulates steroidogenesis (Seger et al, 2001;Woods et al, 2007). Other pathways have also been implicated in EGF signaling in the ovary of different species.…”

“…Other pathways have also been implicated in EGF signaling in the ovary of different species. EGF has been reported to activate PI3K/Akt in human granulosa cells (Zhang et al, 2010), PKC in the chicken ovary (Woods et al, 2007), and p38 MAPK in ovarian cancer cells (Zhou et al, 2007). To understand the intracellular signaling mechanisms that underlie EGF stimulation of activin subunits in the zebrafish ovary, we undertook this study using pharmacological approach, Western blot and immunohistochemical (IHC) staining, and our results provide evidence that EGF signaling in the ovary involves activin system and it controls the expression of three activin subunits via diverse signal transduction pathways.…”

Effect of epidermal growth factor on follicle-stimulating hormone-induced proliferation of granulosa cells from chicken prehierarchical follicles

“…Many reports suggested that AG1478 attenuated FSH-induced actions in ovary from various species. For example, AG1478 augmented FSHR mRNA expression and initiated progesterone production in undifferentiated granulosa cells of chicken ovary (Woods et al, 2007), and blocked meiotic resumption induced by FSH and amphiregulin in mouse cumulus cell-enclosed oocytes (Downs and Chen, 2008). We showed that AG1478 blocked FSHstimulated granulosa cell proliferation.…”