Follicle-stimulating hormone regulates expression and activity of epidermal growth factor receptor in the murine ovarian follicle

Abstract

Fertility depends on the precise coordination of multiple events within the ovarian follicle to ensure ovulation of a fertilizable egg. FSH promotes late follicular development, including expression of luteinizing hormone (LH) receptor by the granulosa cells. Expression of its receptor permits the subsequent LH surge to trigger the release of ligands that activate EGF receptors (EGFR) on the granulosa, thereby initiating the ovulatory events. Here we identify a previously unknown role for FSH in this signaling cascade. We show that follicles of Fshb −/− mice, which cannot produce FSH, have a severely impaired ability to support two essential EGFRregulated events: expansion of the cumulus granulosa cell layer that encloses the oocyte and meiotic maturation of the oocyte. These defects are not caused by an inability of Fshb −/− oocytes to produce essential oocyte-secreted factors or of Fshb −/− cumulus cells to respond. In contrast, although expression of both Egfr and EGFR increases during late folliculogenesis in Fshb +/− females, these increases fail to occur in Fshb −/− females. Remarkably, supplying a single dose of exogenous FSH activity to Fshb −/− females is sufficient to increase Egfr and EGFR expression and to restore EGFR-dependent cumulus expansion and oocyte maturation. These studies show that FSH induces an increase in EGFR expression during late folliculogenesis and provide evidence that the FSH-dependent increase is necessary for EGFR physiological function. Our results demonstrate an unanticipated role for FSH in establishing the signaling axis that coordinates ovulatory events and may contribute to the diagnosis and treatment of some types of human infertility.ertility in mammals depends on the coordinated execution of multiple events within the fully grown ovarian follicle at the time of ovulation (1, 2). The oocyte undergoes meiotic maturation, during which it progresses to metaphase II of meiosis and acquires the ability to begin embryonic development (3). Concomitantly, the layer of granulosa cells (GCs) immediately surrounding the oocyte, termed the "cumulus," undergoes a process termed "expansion," which is required for sperm to penetrate this layer and reach the oocyte (4-7). At the perimeter of the follicle, an inflammatory response associated with rupture of the follicular wall permits the cumulus-oocyte complex (COC) to escape from the follicle and enter the oviduct where fertilization will occur. These events are triggered by the preovulatory release of luteinizing hormone (LH), which acts on LH receptors (LHCGR) on the mural GCs that line the interior wall of the fully grown follicle (8).Recent studies have identified a key downstream effector of LH activity at ovulation. Binding of LH to LHCGR triggers the release of the EGF-related peptides amphiregulin (AREG, betacellulin (BTC), and epiregulin (EREG) (9-11). These bind to EGF receptors (EGFRs) located on both the mural and cumulus GCs (12-19) and activate MAPK3/1 as well as other signaling networks (20-28). Considerable evidence su...

Extracellular Signal-regulated Kinase (ERK)-dependent Phosphorylation of Y-Box-binding Protein 1 (YB-1) Enhances Gene Expression in Granulosa Cells in Response to Follicle-stimulating Hormone (FSH)

“…Lhcgr encodes the LH receptor that is required for ovulation, cumulus cell expansion, and the resumption of meiosis (67); Cyp11a1 encodes cytochrome P450 side chain cleavage, the rate-limiting enzyme for progesterone biosynthesis (18,68); the EGFR contributes to LH-stimulated expansion of cumulus granulosa cells, resumption of meiosis, and ovulation (27,69,70); Cyp19a1 encodes aromatase, the rate-limiting enzyme in estrogen biosynthesis (71); Inha encodes for the inhibin hormone subunit inhibin-␣ that inhibits FSH expression by the anterior pituitary (72); Hsd17b1 encodes the enzyme that converts androstenedione and estrone to testosterone and estradiol-17␤, respectively, and is required for normal ovulation and corpus luteum formation (73); and Pappa encodes a secreted metalloproteinase that cleaves IGF-binding proteins and contributes to estrogen and progesterone biosynthesis and to ovulation (74).…”

“…Our recent results, however, suggest the PI3K/AKT pathway is likely regulating additional transcriptional modulators, based on the ability of exogenous insulin-like growth factor 1 (IGF 1 ) at concentrations Ͼ1 ng/ml to synergize with FSH to enhance gene expression without further increasing the phosphorylation of FOXO1 (Ser 256 ) (19). Strong evidence in cancer cells identified YB-1 as an AKT target (20 -23) that, upon phosphorylation on Ser 102 , acts as a transcription factor to promote expression of genes such as Egfr (21, 24 -26), a recognized FSH gene target (27).…”

Promotion of EGF receptor signaling improves the quality of low developmental competence oocytes

“…During the late phase of antral folliculogenesis, prior to the LH surge, FSH binds to the FSH receptor and stimulates the expression of LH receptors (LHR) on mural granulosa cells (Erickson et al, 1979) and epidermal growth factor receptors (EGFR) on cumulus cells (El-Hayek et al, 2014). Oocyte meiotic maturation occurs during the period between the LH surge and ovulation.…”

Gene Expression and Apoptosis Levels in Cumulus Cells of Patients with Polymorphisms of FSHR and LHB Undergoing in Vitro Fertilization Program

“…Among the marker genes tested, EGFR appears to undergo the more varying modifications with respect to the specific FSHR SNP, when coupled to p.R28-p.T35 LHB aplotype, being up-regulated in p.T307-N680 carriers and down-regulated in p.A307-S680 carriers, whereas AREG expression was always found increased in the recessive models of FSHR . It is known that FSH triggers the expression of both EGFR , thereby stimulating EGF sensitivity, and LHCGR which, in turn, elicits the production of the EGF-related peptides, such as AREG and EREG, and the accumulation of EGFR on the plasmalemma of granulosa cells [38, 39]. In the mouse, the LH-mediator AREG is responsible of the expression of several genes controlling follicular growth and steroidogenesis and also of its own synthesis by paracrine stimulation [40].…”