Portrait of an oocyte: our obscure origin

Abstract

Oocytes play a pivotal role in the cycle of human life. As we discuss here, after emerging from germline stem cells in the fetus, they grow in a follicular niche in which development is harmonized for timely ovulation and hormone secretion after puberty. Most human oocytes have poor developmental competence and are peculiarly vulnerable to chromosomal malsegregation, especially as women pass the optimal years of fertility and may begin to turn to assisted reproductive technologies (ARTs) and egg donation. Research needs to focus on the molecular factors involved and the environmental niche required for optimal development of oocytes, with the aim of increasing their numbers and quality for ARTs, since these are the factors that so often limit human fertility.

Figure 1. Schematic diagram of follicle maturation in the ovary.

Prior to birth, primordial germ cells migrate to the developing ovary and, after a period of proliferation, they enter meiosis I. At birth the ovary contains many primordial-stage follicles, which contain small, non-growing oocytes surrounded by a single granulosa cell layer. These follicles develop in the step-wise manner depicted to become preovulatory, Graafian-stage follicles, which contain a fully grown oocyte. Oocytes reach metaphase II of meiosis after the ovulatory surge of gonadotropins that occurs mid–menstrual cycle. Meiosis is only completed upon oocyte fertilization.

Figure 2. A panel showing 6 human oocytes harvested after ovarian stimulation for assisted conception that are either pre- or post-fertilization and vary in quality and developmental potential.

(A) Normal, metaphase II stage with first polar body (indicated by white line). (B) Unfertilized oocyte containing many large vacuoles (V). (C) Pronuclear stage with extensive cytoplasmic fragmentation (F). (D) Oocyte with a single pronucleus (P) after fertilization by ICSI (haploid). (E) Triploid zygote with 2 large and 1 small pronucleus, suggesting that fertilization was dispermic. (F) Tetraploid zygote with four pronuclei after presumptive trispermic fertilization. A, B, D, and F reproduced with permission from An Atlas of Human Gametes and Conceptuses (50). C and E reproduced with permission from An Atlas of Human Blastocysts (141).

Figure 3. A rare case of mature human oocytes uniformly zona-free.

(A) The zona pellucida was completely absent in all oocytes harvested from a patient with infertility. (B and C) The eggs formed pronuclei after ICSI and cleaved to the 2–4 cell stage in vitro (B), although they never generated an ongoing pregnancy when replaced in the uterus (C), even after transfer to evacuated zonae. Reproduced with permission from An Atlas of Human Gametes and Conceptuses (50).

Figure 4. Diagrammatic representation of the suppression of mRNA translation in RNP complexes in oocytes.

After the freshly transcribed and spliced transcript is incorporated into a RNP complex, it can either be translated directly or enter a prolonged period of translational dormancy. Transcripts that can be stored contain a CPE at the 3′-untranslated end, to which the protein CPEB binds. Phosphorylation of the latter causes release of PARN from the complex, enabling GLD2 to elongate the poly(A) and hence facilitate translation by interaction with other proteins. In dormant mRNAs, another CPEB-associated protein, maskin, inhibits an initiation factor (eIF4G) required for recruiting the 40S ribosomal subunit to the 5′ end of the mRNA by binding the cap-binding eukaryotic initiation factor (4E). 40S, 40S ribosomal subunit.

Figure 5. Schematic illustration of molecular and cellular maturation of human oocytes.

Stages of development from initiation of oocyte growth in small follicles through meiotic maturation and fertilization to cleavage. Competence to resume meiosis is reached in fully grown oocytes several days before ovulation. Transcription becomes silent after the resumption of meiosis until the 4- to 8-cell stage, and gene expression is dependent on translation of stored mRNAs until embryonic genome activation occurs 3–4 days later. Protein synthesis increases to a plateau when the oocyte is fully grown. Progression through stages of meiosis depends on phosphorylation changes in MPF and MAPK. When the oocyte is cytoplasmically mature, oscillations of [Ca²⁺]_i released from stores in the ER are triggered by the fertilizing sperm.