Meiosis comprises fundamental processes that permit sexual reproduction and species evolution. In addition to producing haploid gametes, it provides for a stochastic distribution of maternally and paternally inherited chromosomes, which undergo allelic recombination thereby increasing genetic variability in the next generation. Thus it provides for diversity within a population, and is essential for the formation of euploid germ cells that will contribute to a euploid healthy embryo after fertilization. Meiosis is therefore the basis for maintaining genomic integrity, high developmental potential, and health of the embryo and offspring, and normal fertility in males and females [1,2]. Furthermore, it is the basis of changes in the genome that are important for adaptation and evolution of species.

Introduction

Cellular interactions are known to be essential not only in mammalian developing tissues and organs, but also during steady-state maintenance phases. In the mammalian ovary, cellular interactions are particularly important since follicle development is continuously initiated, during childhood and adulthood, until the follicle pool drops below a poorly understood threshold in menopause. In this context, the germ cell–soma interface is of major relevance since it is at this level that a fine tuning must take place to allow for correct ovarian follicle development and the full oocyte functionality, known as oocyte competence acquisition. This includes complex differentiation processes of the somatic cells, fine tuning in response to growth factors and hormones, and the regulation of meiotic arrest and metabolism to the demand of the growing and maturing oocyte.

Although the zona pellucida, an oocyte-specific extracellular layer, intercalates between oocytes and the innermost layer of cumulus granulosa cells (corona radiata), unique cellular structures are present at this level that emanate from the granulosa cell, extend across the zona pellucida, and reach direct contact with the oocyte's plasma membrane. These structures, known as the transzonal projections (TZPs), may contain cytoskeletal components, such as tubulin and/or actin, and possess membrane junctions such as gap and adhesion junctions, and cell organelles such as mitochondria. Between neighboring granulosa cells similar specialized junctions exist that allow direct cell–cell signaling but also permit nutrient access to the oocyte.

When approached by Nick Dunton of Cambridge University Press to edit the second edition of The Biology and Pathology of the Oocyte, my response was an emphatic yes, providing my co-editor Roger Gosden could be enticed from retirement. He agreed and we both wanted Ursula Eichenlaub-Ritter to be the third editor because we admired her expertise in the basic biology of the oocyte and her ability to get the job done. There has been incredible progress in the knowledge of the oocyte and applications for medicine that have regularly appeared since the first edition. We considered the areas of reproductive technology – IVF – and the areas of reprogramming somatic cell phenotype as spin-offs of the progress made in oocyte biology. Both these areas received Nobel Prizes in the last few years and are included in the contributions for the second edition. We were fortunate to have John Gurdon open the second edition the year (2013) after he won the Nobel Prize in Physiology or Medicine. He and his coauthor set the scene for a rather different perspective of the power and influence of the oocyte in modern biology. The contributors invited for the second edition are exceptional in their areas of oocyte biology, pathology, and applications to biotechnology and medicine. We think they have captured the excitement of the fast-moving frontier of the oocyte field.

The second edition will enthuse the reader interested in how the oocyte is formed, its function, and the underlying mechanisms of what is the most extraordinary cell in the body. It remains the germinal link from generation to generation and must undergo the most elaborate series of changes to be ready to accept the genomic contribution of the most differentiated of all cells – the sperm. The oocyte must then enter the developmental program that enables an organism to arise with extremes in patterning and lineage differentiation consistent with the species of origin. In this exquisitely crafted program of development, it is possible to intervene to manipulate the oocyte for purposes of solving human infertility, to clone animals, develop pluripotent embryonic stem cells, and reprogram cell commitment in fully differentiated cells in animals including the human – so-called induced pluripotent stem cells (iPSCs). As a consequence we are able to address human infertility and avoid some of the worst inheritable genetic diseases, enable advances in selective animal breeding, and potentially address many human pathologies by using stem cell therapies.

Introduction

Separation of chromosomes in meiosis is a well-guarded process such that errors in chromosome segregation are rare events. For instance, only 1 in every 100000 divisions in yeast is associated with non-disjunction. Aneuploidy in germ cells of mammals like the mouse is generally much higher, in the range 0.5–1% [1]. Furthermore, there is a gender-specific difference in susceptibility to meiotic errors during germ cell formation in mammals, particularly in humans. On average, only 1–4% of sperm in healthy men have numerical chromosomal aberrations, while on average about 20% of all human meiosis II oocytes are aneuploid [1–4]. The correlation between the incidence of the birth of a trisomic child with Down's syndrome and maternal age was first recognized in 1933 by Penrose [5], confirmed by chromosomal analysis of spontaneous abortions and live births and, since the introduction of assisted reproduction, by evidence from polar bodies, oocytes, and embryos (e.g., [3, 6–8]). However, the cause(s) of the extraordinary susceptibility of aging oocytes to meiotic errors was obscure until recently.

Meiotic stages at which errors may occur

In typical mitosis there is division of sister chromatids derived from replication of each chromosome, and each pair therefore carries the same alleles along their arms (Figure 28.1A). In contrast, in meiosis I the two originally paternally and maternally derived homologs, each containing two sister chromatids, separate during first meiotic division (termed reductional division, Figure 28.1B, Ciii). They are normally physically attached to each other by at least one chiasma from recombination between sister chromatids of parental homologs (indicated by X in Figure 28.1B, Ci, Ciii). Chiasmata are held in place by cohesion between sister chromatid arms and centromeres (Figure 28.1Ci–Ciii) placed on chromatids before S-phase (Figure 28.1Ci), which is maintained until anaphase I (Figure 28.1Ciii, B) (reviewed in [9]). The paternal and maternal alleles along chromatid arms of recombined chromosomes switch left and right of a chiasma or exchange (indicated by different coloring in Figure 28.1B, Ci, E–J). Hence, the distribution of polymorphisms can be used to trace the origin and recombinational history of a chromosome in a zygote or child.

Introduction

Aneuploidy in human oocytes is one of the major aetiological factors in the conception of a trisomic embryo, pre- and postimplantation failure, spontaneous abortion and inheritable genetic disease in the human (Bond and Chandley, 1983; Jacobs, 1992). At least 15-20% of all concepti are estimated to be chromosomally unbalanced (Jacobs, 1992; Eichenlaub-Ritter, 1998), giving rise to reduced developmental potential, congenital abnormalities, mental retardation and reduced life expectancy in affected children. Trisomies most commonly surviving to birth are trisomy 21 (Down's syndrome), trisomy 18 (Edward's syndrome), trisomy 13 (Patau syndrome) and aneuploidies of the sex chromosomes (e.g. 45X, Turner's syndrome). The most common trisomy giving rise to spontaneous abortion is that of trisomy 16 (Hassold et al, 1980).

Since half a century ago, it has been known that aneuploidy increases dramatically with maternal age and is a major factor in reduced fertility in women, but at the physiological level the aetiological factors are still largely unknown. Retrospective and prospective analyses all come to the conclusion that errors predominantly in chromosome segregation at first meiosis of oogenesis and aneuploidy in human oocytes are responsible for chromosomal imbalance in the embryo. Analysis of the origin and recombinational history of extra chromosomes in trisomic conceptuses has by now provided valuable information on the origin of aneuploidy and some correlated factors while the pathological condition of the human oocyte giving rise to a susceptibility to nondisjunction is still under investigation. Information on the origin of errors in chromosome segregation has been obtained in recent years by the genetic analysis of spare or donated human oocytes which become available in assisted reproduction. Moreover, new methods to assess the chromosomal constitution of preimplantation embryos have been developed which provide information on the origin and fate of chromosomally unbalanced embryos. Culture methods and techniques for monitoring spindle formation and chromosome behaviour have improved such that human or other mammalian oocytes can now be matured in vitro and evaluated for pathological features. Naturally occuring mutations and targeted mutagenesis in mice and genetically well-defined organisms like yeast and Drosophila, as well as studies with oocyte cell extracts, have all provided insights into the mechanisms responsible for stringent control and fidelity of chromosome segregation and the aetiological factors in aneuploidy in mammalian oocytes.