Oocyte development: it's all about quality

Abstract

Mammalian fertility depends on the production of an oocyte capable of fertilization and supporting early embryo development. This requires both cytoplasmic and nuclear, i.e. chromosomal, competence, processes that were initiated decades prior to ovulation. Current demographic changes with delayed motherhood are increasingly in conflict with these biological processes. This brief review highlights the key stages in oocyte development, as well as recent findings that continue to inform on how the oocyte is able to maintain function over such a prolonged period. These include minimizing oocyte damage caused by the production of reactive oxygen species, the importance of intercellular communication with the surrounding somatic cells, and the molecular mechanisms that underpin the fidelity of chromosome cohesion and then separation at the resumption of meiosis. Some of these are already approaching clinical testing and interventions, with new approaches in the coming years potentially being able to 'put back the clock' to improve oocyte quality.

Keywords: Aneuploidy; Cohesin; Meiosis; Oocyte; Ovarian development.

Figure 1. The dynamic microenvironment of the human ovary.

The human ovary has the maximum endowment of follicles pre-pubertally and follicles initiate to grow and develop to early antral stages. Following the onset of puberty, all stages of follicle development up to ovulatory stages and corpora lutea are present all embedded within the ovarian stroma. During aging there is depletion of the primordial and growing follicle pool but ovulation continues until the menopausal transition. Aging leads to increased fibrosis of the ovarian stroma which affects the mechanical properties of the ovary that impact on follicle activation and growth.

Figure 2. Development of ovarian follicles from primordial to pre-ovulatory.

Primordial follicles consist of an oocyte arrested at the dictyate stage of Prophase 1 of meiosis surrounded by non proliferating flattened somatic (granulosa) cells. Several factors as listed have been implicated in the maintenance of quiescence (blue line and text) and activation of growth (red arrow and text). Activation of growth is characterized by the oocyte being surrounded by a complete layer of cuboidal granulosa cells (Primary stage). Paracrine factors such as activin stimulate proliferation of granulosa cells to form multi-laminar structures (pre-antral) which are surrounded by differentiated thecal cells. Pre-antral follicles undergo a morphogenetic transition to form a filled antral cavity with mural granulosa cells lining the wall of the follicle and cumulus granulosa cells surrounding the oocyte. Under the regulation of Follicle Stimulating Hormone (FSH) antral follicles undergo rapid growth to reach pre-ovulatory stages with the oocyte-cumulus complex being released at ovulation in response to Luteinising Hormone (LH) signalling.

Figure 3. Communication network within the follicle.

Communication between all cell types (oocyte, cumulus and mural granulosa cells and theca) within the growing follicle is facilitated through gap junctions and transzonal projections (TZPs) that form a syncytium to facilitate bi-directional communication (A) mediated by paracrine factors (B). Maintenance of this communication network is essential to support meiotic arrest, follicle and oocyte growth and granulosa cell differentiation through paracrine signalling (B). Re-initiation of meiosis requires the activation of maturation-promoting factor (MPF: a heterodimer composed of CDK1 and Cyclin B (B1, B2 and B3) and this needs to be inhibited to prevent premature resumption of meiosis. Inhibition is dependent upon intracellular cAMP levels being elevated in the oocyte with oocyte production of cAMP being the major pathway in regulating meiotic arrest with somatic cells playing an indirect role in maintaining elevated cAMP levels via cGMP from the granulosa cells inhibiting PDE3 activity within the oocyte (B). This is mediated via the natriuretic peptide C/natriuretic peptide receptor 2 (NPPC/NPR2) system. C-type natriuretic peptide (CNP) is produced in mural granulosa cells and its receptor NPR2 is expressed within cumulus granulosa cells. The production of cGMP in the granulosa cells inhibits the degradation of cAMP by inhibiting phosphodiesterase (PDE3) activity in the oocyte (B).

Figure 4. Error-free and erroneous meiotic chromosome segregation.

Top schematic shows accurate segregation of a homologous chromosome pair in the two meiotic divisions. Bottom schematic shows the effect of cohesin deterioration in an aged oocyte.