The epidermal growth factor network: role in oocyte growth, maturation and developmental competence

Abstract

Background: The LH surge induces great physiological changes within the preovulatory follicle, which culminate in the ovulation of a mature oocyte that is capable of supporting embryo and foetal development. However, unlike mural granulosa cells, the oocyte and its surrounding cumulus cells are not directly responsive to LH, indicating that the LH signal is mediated by secondary factors produced by the granulosa cells. The mechanisms by which the oocyte senses the ovulatory LH signal and hence prepares for ovulation has been a subject of considerable controversy for the past four decades. Within the last 15 years several significant insights have been made into the molecular mechanisms orchestrating oocyte development, maturation and ovulation. These findings centre on the epidermal growth factor (EGF) pathway and the role it plays in the complex signalling network that finely regulates oocyte maturation and ovulation.

Objective and rationale: This review outlines the role of the EGF network during oocyte development and regulation of the ovulatory cascade, and in particular focuses on the effect of the EGF network on oocyte developmental competence. Application of this new knowledge to advances in ART is examined.

Search methods: The PubMed database was used to search for peer-reviewed original and review articles concerning the EGF network. Publications offering a comprehensive description of the role of the EGF network in follicle and oocyte development were used.

Outcomes: It is now clear that acute upregulation of the EGF network is an essential component of the ovulatory cascade as it transmits the LH signal from the periphery of the follicle to the cumulus-oocyte complex (COC). More recent findings have elucidated new roles for the EGF network in the regulation of oocyte development. EGF signalling downregulates the somatic signal 3'5'-cyclic guanine monophosphate that suppresses oocyte meiotic maturation and simultaneously provides meiotic inducing signals. The EGF network also controls translation of maternal transcripts in the quiescent oocyte, a process that is integral to oocyte competence. As a means of restricting the ovulatory signal to the Graffian follicle, most COCs in the ovary are unresponsive to EGF-ligands. Recent studies have revealed that development of a functional EGF signalling network in cumulus cells requires dual endocrine (FSH) and oocyte paracrine cues (growth differentiation factor 9 and bone morphogenetic protein 15), and this occurs progressively in COCs during the last stages of folliculogenesis. Hence, a new concept to emerge is that cumulus cell acquisition of EGF receptor responsiveness represents a developmental hallmark in folliculogenesis, analogous to FSH-induction of LH receptor signalling in mural granulosa cells. Likewise, this event represents a major milestone in the oocyte's developmental progression and acquisition of developmental competence. It is now clear that EGF signalling is perturbed in COCs matured in vitro. This has inspired novel concepts in IVM systems to ameliorate this perturbation, resulting in improved oocyte developmental competence.

Wider implications: An oocyte of high quality is imperative for fertility. Elucidating the fundamental molecular and cellular mechanims by which the EGF network regulates oocyte maturation and ovulation can be expected to open new opportunities in ART. This knowledge has already led to advances in oocyte IVM in animal models. Translation of such advances into a clinical setting should increase the efficacy of IVM, making it a viable treatment option for a wide range of patients, thereby simplifying fertility treatment and bringing substantial cost and health benefits.

Keywords: ART; amphiregulin; betacellulin; epidermal growth factor receptor; epiregulin; fertility; folliculogenesis; oocyte; ovary; ovulation.