Regulation of the aryl hydrocarbon receptor activity in bovine cumulus-oocyte complexes during in vitro maturation: The role of EGFR and post-EGFR ERK1/2 signaling cascade.

The aryl hydrocarbon receptor (AhR) has been extensively characterized as an environmental sensor with major roles in xenobiotic-induced toxicity. Evidence is accumulating that these functions serve as adaptive mechanisms overlapping its physiological roles. We previously described a critical role of constitutive AhR activation for the correct progress of mammalian oocyte maturation but the signaling pathway through which AhR controls maturation remains unclear. The aim of this study was to investigate whether the AhR interacts with the epidermal growth factor receptor (EGFR) and p42/44 extracellular regulated kinases (ERK1/2), both key factors in the signaling network that finely regulates the oocyte maturation. As experimental model we used bovine cumulus-oocyte complexes (COCs) during in vitro maturation (IVM). Blocking ERK1/2 signaling in COCs during IVM with the specific EGFR inhibitor AG1478 or the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 downregulated the expression of the AhR-target gene Cyp1a1. Inhibition of AhR activity was associated with a reduction in the oocytes' ability to progress in meiosis resumption. In contrast, exposure to the AhR antagonist resveratrol reduced both CYP1A1 expression and the oocytes' maturation competence, without affecting ERK1/2 signaling. These findings strongly indicate the EGFR/ERKs signaling network as an upstream regulator of the AhR activation in COCs, offering a new understanding of the finely tuned physiological mechanism leading to oocyte maturation. This information may provide fresh opportunities for improving oocyte in vitro maturation, and therefore boosting the efficiency of assisted reproduction techniques in mammals.

Pocar P ，Berrini A ，Di Giancamillo A ，Fischer B ，Borromeo V ... -  《-》

Constitutive expression of CYP1A1 in bovine cumulus oocyte-complexes in vitro: mechanisms and biological implications.

Pocar P ，Augustin R ，Fischer B 《ENDOCRINOLOGY》

Exogenous Ganglioside GT1b Enhances Porcine Oocyte Maturation, Including the Cumulus Cell Expansion and Activation of EGFR and ERK1/2 Signaling.

Kim JW ，Park HJ ，Yang SG ，Kim MJ ，Kim IS ，Jegal HG ，Wee G ，Yang HY ，Park JJ ，Choo YK ，Koo DB ... -  《-》

Regulation of aryl hydrocarbon receptor activity in porcine cumulus-oocyte complexes in physiological and toxicological conditions: the role of follicular fluid.

Nestler D ，Risch M ，Fischer B ，Pocar P ... -  《REPRODUCTION》

Interaction of the EGFR signaling pathway with porcine cumulus oocyte complexes and oviduct cells in a coculture system.

It has become increasingly recognized that coculture has a beneficial effect on the in vitro maturation (IVM) of oocytes and embryo development in many species. However, these effects of coculture on IVM have been documented only for their positive conditioning roles without any evidence on the precise mechanisms underlying the action of coculture systems on the development of cumulus oocyte complexes (COCs). It has been suggested that the epidermal growth factor receptor (EGFR) signaling pathway is important for development of COCs, mediated by several epidermal growth factor (EGF)-like proteins with downstream mitogen-activated protein kinase 1/3 signaling. Therefore, we hypothesized that canine oviduct cells (OCs) in a coculture system, which shows improvement of oocyte quality in several species, are associated with EGFR signaling by exposure to progesterone (P4; imitating its production before ovulation and its continuous increase while oocytes reside in the oviduct to complete maturation in dogs). We designed three experimental groups: control, OCs coculture exposed to P4, and OCs coculture without exposure to P4. The result showed that the OCs coculture exposed to P4 strongly expressed EGF-like proteins and significantly improved COCs and subsequent embryo development. Furthermore, the expression of EGFR-related genes in cumulus cells and GDF9 and BMP15 in oocytes was upregulated in the P4-treated group. This study provides the first evidence that OCs exposed to P4 can induce strong expression of EGF-like proteins, and OCs effectively mediate improved porcine COCs development and subsequent embryo development by altering EGFR signaling related mRNA expression.

Lee SH ，Oh HJ ，Kim MJ ，Setyawan EMN ，Lee BC ... -  《-》