Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events

Abstract

Infertility affects ~7% of couples of reproductive age with little change in incidence in the last two decades. ART, as well as other interventions, have made major strides in correcting this condition. However, and in spite of advancements in the field, the age of the female partner remains a main factor for a successful outcome. A better understanding of the final stages of gamete maturation yielding an egg that can sustain embryo development and a pregnancy to term remains a major area for improvement in the field. This review will summarize the major cellular and molecular events unfolding at the oocyte-to-embryo transition. We will provide an update on the most important processes/pathways currently understood as the basis of developmental competence, including the molecular processes involved in mRNA storage, its recruitment to the translational machinery, and its degradation. We will discuss the hypothesis that the translational programme of maternal mRNAs plays a key role in establishing developmental competence. These regulations are essential to assemble the machinery that is used to establish a totipotent zygote. This hypothesis further supports the view that embryogenesis begins during oogenesis. A better understanding of the events required for developmental competence will guide the development of novel strategies to monitor and improve the success rate of IVF. Using this information, it will be possible to develop new biomarkers that may be used to better predict oocyte quality and in selection of the best egg for IVF.

Figure 1

Functional analysis of patterns of mRNA translation during oocyte maturation. A and B. Gene ontology (GO) analysis of mRNAs that are released from the polysomes (A) or recruited from the polysome fraction (B) during oocyte maturation. The analysis was performed comparing germinal vesicle and metaphase II polysome array data. N = 6. (C) Scheme of the function of timed translation of maternal mRNA. The components were derived from GO analysis and from manual curation of the data. The function of these regulated transcripts has been confirmed experimentally for component of the cell cycle, chromatin remodellers and secretory products of the oocyte (Chen et al., 2011, 2013; Cakmak et al., 2016).

Figure 2

Contrasting patterns of total mRNA levels versus mRNA bound to ribosomes during oocyte maturation. (A) Levels of the developmental pluripotency associated 3 (Dppa3) and testis expressed 19.1 (Text19.1) mRNA during oocyte maturation. The data were obtained by measuring total mRNA levels by quantitative PCR (qPCR). (B) Dppa3 and Tex19.1 mRNA bound to ribosomes measured by ribosome immunoprecipitation and quantification of the mRNA recovered in the pellet by qPCR. Details of the technique are reported in Sousa Martins et al. (2016). Note that no differences in transcript levels or transcript behavior are detected when using total mRNA (A). However, when mRNAs bound to ribosome are measured, clear differences are found: Dppa3 is constitutively translated during maturation whereas Tex19.1 mRNA translation increases up to 6-fold during oocyte maturation (B). (C) Pattern of ribosome loading on the mRNA coding for Mos, a kinase critical for meiotic maturation. Mos mRNA translation increases after germinal vesicle (GV) breakdown (GVBD), reaches a maximum at the end of metaphase I (MI), remains steady until metaphase II (MII), and its translation is shut off during egg activation. The data are composites of polysome arrays and ribosome immunoprecipitation data.

Figure 3

Dynamic changes in components of the chromatin during oocyte maturation due to contrasting patterns of components translation. Schematic representation of the components of the nucleosome, cohesins, and the chromatin switch/sucrose non-fermentable (SWI/SNF) complex are reported on top. The lower panel reports the level of mRNAs bound to polysomes for the above components as well as additional chromatin remodelers thought to function at the maternal to zygote transition. The data are derived from deposited data (GEO dataset Accession: GSE35106 ID:200 035 106). SMC1: Structural Maintenance Of Chromosomes 1; SMC3: Structural Maintenance Of Chromosomes 3; REC8: REC8 Meiotic Recombination Protein; RAD21: Rad21 (S.Pompe) Homolog (Scc1); SCC1: alternative name for RAD21 (used interchangeably) ; PDS5A: Cohesin Associated Factor A; WAPAL: Wings Apart-Like Homolog; SORORIN: Cell Division Cycle-Associated Protein 5 (CDCA5); STAG1: Stroma Antigen 1; STAG2: Stromal Antigen 2; POLYBROMO1: BRG1-Associated Factor 180 (Baf180); SMARCD1: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily D, Member 1; SMARCB1: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1; SMARCE1: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily E, Member 1; SMARCC1: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin Subfamily C Member 1; ARID1A: AT-Rich Interaction Domain 1A (BAF250); AD REQUIEM: Double PHD Fingers 2; BRG1: Brahma-related gene-1 (known as SMARCA4) ; SMARCA4: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4 (BRG1); SMARCA5: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 5; SMARCD2: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily D, Member 2; ACTl6A: Actin Like 6A; ARID2: AT-Rich Interaction Domain 2; ARID1B: AT-Rich Interaction Domain 1B; SMARCA2: SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2; JARID2: Jumonji And AT-Rich Interaction Domain Containing 2; SUV39H2: Suppressor Of Variegation 3–9 Homolog 2; BMI1: Polycomb Ring Finger Proto-Oncogene; TET3: Tet Methylcytosine Dioxygenase 3.

Figure 4

Integration of cumulus–oocyte functions via local feedbacks targeting maternal mRNA translation in the oocyte. Regulation of maternal mRNA translation in the oocyte plays a critical role in mediating protein secretion and these feedback regulations. In the follicle microenvironment, there is bidirectional exchange of signals between the oocyte and the surrounding somatic cells. The signals from the somatic cells stimulate the fully grown oocytes to increase translation of selected mRNAs. In turn, oocyte secreted factors may control cumulus cell function. AREG, amphiregulin; OSF, oocyte secreted factor; EGFR, epidermal growth factor receptor.