Luteinizing Hormone-Dependent Activation of the Epidermal Growth Factor Network Is Essential for Ovulation

Abstract

In the preovulatory ovarian follicle, mammalian oocytes are maintained in prophase meiotic arrest until the luteinizing hormone (LH) surge induces reentry into the first meiotic division. Dramatic changes in the somatic cells surrounding the oocytes and in the follicular wall are also induced by LH and are necessary for ovulation. Here, we provide genetic evidence that LH-dependent transactivation of the epidermal growth factor receptor (EGFR) is indispensable for oocyte reentry into the meiotic cell cycle, for the synthesis of the extracellular matrix surrounding the oocyte that causes cumulus expansion, and for follicle rupture in vivo. Mice deficient in either amphiregulin or epiregulin, two EGFR ligands, display delayed or reduced oocyte maturation and cumulus expansion. In compound-mutant mice in which loss of one EGFR ligand is associated with decreased signaling from a hypomorphic allele of the EGFR, LH no longer signals oocyte meiotic resumption. Moreover, induction of genes involved in cumulus expansion and follicle rupture is compromised in these mice, resulting in impaired ovulation. Thus, these studies demonstrate that LH induction of epidermal growth factor-like growth factors and EGFR transactivation are essential for the regulation of a critical physiological process such as ovulation and provide new strategies for manipulation of fertility.The luteinizing hormone (LH) surge plays a central role in promoting a cascade of events in ovarian preovulatory follicles that are essential for the ovulation of a fertilizable oocyte. Acting through LH-chorionic gonadotropin (LH-CG) receptors (LHRs) (LHR is a member of the G protein-coupled receptor superfamily encoded by Lhcgr), LH induces reprogramming of the gene expression profiles of follicular somatic cells (theca and granulosa cells), changes in the secretory properties of the cumulus cells surrounding the oocyte and cumulus expansion, oocyte reentry into the meiotic cell cycle, and follicle rupture (7, 41). LHRs are highly expressed on the granulosa cells lining the antral cavity of preovulatory follicles (mural granulosa cells) and on the external theca cells that are in continuity with the surrounding stroma. However, within preovulatory follicles, oocytes and cumulus cells that are profoundly affected by the LH surge express few or no LHRs and fail to respond when directly exposed to LH in vitro (37).To explain how LH signals are propagated from the periphery toward the cumulus oocyte complex (COC), a model has been proposed whereby factors released by mural granulosa cells function in an autocrine and paracrine manner to transduce the LH effects within the follicle (34). Secretion of bioactive growth factors from the oocyte to affect somatic cells is well established (27,30); conversely, the paracrine signals originating from the somatic cells and affecting oocytes have long been sought but are largely unknown. Recently, we have proposed that intrafollicular release of members of the epidermal growth factor (EGF)-like family (34) may fulfill this ...

Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process

“…Regulation of bovine preovulatory follicular ADAM17 and AREG mRNAs following the LH surge Extensive evidence in rodents supports a key role of EGFlike growth factors in mediating LH action in preovulatory follicles (Ben-Ami et al 2006, Conti et al 2006, Hsieh et al 2007, Panigone et al 2008. Moreover, ADAMs, such as ADAM10 function as sheddases and play critical roles in releasing such EGF receptor ligands (Blobel 2005).…”

Efeito do fator de crescimento epidermal (EGF) na maturação in vitro de oócitos caninos

“…De acordo com Lonergan et al (1996), a suplementação com EGF em diferentes concentrações (1-100 ηg/mL), durante a MIV de oócitos bovinos, melhora a maturação oocitária, expansão das células do cumulus, taxa de fertilização e desenvolvimento embrionário. Segundo Hsieh et al (2007), os fatores de crescimento ligantes de EGF são mediadores parácrinos de sinalização do LH durante a ovulação. Em oócitos caninos, a suplementação com 20 ηg/ mL de EGF proporcionou melhores taxas de metáfase II (KIM et al, 2004).…”

Mutations of the lutropin/choriogonadotropin receptor that do not activate the phosphoinositide cascade allow hCG to induce aromatase expression in immature rat granulosa cells

“…The EGF-like growth factor(s) that mediate these actions of gonadotropins are not known and is thus indicated as "EGF-like" in the figure. Epiregulin has been shown to be a mediator of the actions of hCG in the mouse ovary (Hsieh et al, 2007;Park et al, 2004) and is the most abundant EGF-like growth factor in the rat ovary (Andric and Ascoli, 2006;Ashkenazi et al, 2005). We have previously shown that hFSH and hCG can increase epiregulin mRNA when acting on cells expressing a low or high density of their cognate receptors, but epiregulin mRNA is much Table 1 Effects of gonadotropins on second messengers, ERK1/2 phosphorylation and aromatase expression in immature granulosa cells expressing the endogenous FSHR only or the endogenous FSHR and the recombinant hLHR or hLHR-LD Primary cultures of immature granulosa cells were infected with Ad-βgal at 300 MOI, a mixture of Ad-hLHR at 200 MOI plus Ad-βgal at 100 MOI (hLHR), or Ad-hLHR-LD at 300 MOI (LD).…”