Meiosis

Sexual reproduction represents a key event in evolution, since it greatly increases genetic diversity thereby accelerating the development of complex life (Colegrave, 2012). The characteristic of sexual reproduction is the fusion of gametes (egg and sperm in vertebrates) to recombine the parental genomes into a new genotype. Upon fertilization of an egg with a sperm the two haploid sets of chromosomes from father and mother fuse to form a diploid zygote. In order to keep the chromosome set of a diploid organism constant a prerequisite for sexual reproduction is the formation of haploid gametes via a specialized cell division called meiosis (Morgan, 2007). Among eukaryotes one can find substantial differences in the structures and mechanisms involved in the production of germ cells (Loidl, 2016). In the following we describe the mammalian meiosis.

1.4.1. Specific features of meiosis

Meiosis allows the formation of haploid gametes from a diploid precursor cell by one round of DNA replication followed by two successive rounds of chromosome segregation (Figure 5).

In the first round of chromosome distribution (meiosis I) the homologous chromosomes are segregated reducing the ploidy of the daughter cells. The sister chromatids are segregated in the second meiotic division (meiosis II). For separation of the homologous chromosomes in meiosis I the sister kinetochores attach to one pole of the spindle. How this so-called mono-orientation is exactly achieved remains to be determined but probably involves the physical fusion of the kinetochores (Duro and Marston, 2015). Recently Kim et al. identified the protein Meikin, which localizes to kinetochores exclusively in meiosis I and seems to be involved in the kinetochore fusion. Mice lacking Meikin are completely infertile and have severe defects in mono-orientation (Kim et al., 2015). In contrast to mitosis, the homologous chromosomes have to be physically linked to allow their correct distribution in meiosis I. During prophase of the first meiotic division the homologs align and recombination events between paternal and maternal chromosomes form chiasmata, which tether the chromosomes (Klug, 2012; Morgan, 2007).

Introduction

Figure 5: Overview of mitosis and meiosis

In mitosis one round of chromosome segregation produces two diploid cells. In meiosis the first of two chromosome distribution events reduces the ploidy as the homologous chromosomes are segregated into the daughter cells. For details see text.

The changing shapes of the chromosomes observable by light microscopy during prophase I led to its subdivision into distinct stages. In the first stage of prophase I, the so called leptonema, chromosomes start to condense and to pair. In the following zygonema the chromosomes are shortened and the synaptonemal complex (SC) starts to form. The SC is a proteinaceous structure, which tethers the homologous chromosomes together and facilitates generation of chiasmata(Zickler and Kleckner, 1999). Additional compaction of the chromosomes and disassembly of the SC occurs in pachynema. In the next step, the diplonema, the distance between chromosomes increases. The final stage is characterized by nuclear envelope breakdown and formation of the meiotic spindle and is termed diakinesis

Introduction

(Klug, 2012). In the following metaphase I the homologs are oriented for the correct segregation in anaphase I. The spindle microtubules depolymerize, the nuclear envelope may re-form (depending on the organism) and cytokinesis takes place in telophase I. The following meiosis II begins with nuclear envelope breakdown in prophase II followed by alignment of the chromosomes in metaphase II and segregation of sister chromatids in anaphase II. It ends up with 4 haploid cells in telophase II.

There are profound differences in meiosis of male (spermatogenesis) and female (oogenesis) mammals. Cells that currently pass through meiosis are called spermatocytes or oocytes, respectively. The initiation of spermatogenesis takes place during puberty and the production of sperm continues the complete life span of the male individual. Spermatogenesis is a continuous process that ends up with four haploid, functional sperm cells. Oogenesis in contrast, produces only one functional egg, since both meiotic divisions are highly asymmetric.

During telophase I one set of homologs is abscised with a very small amount of cytoplasm forming the first polar body. A subsequent asymmetric cell division in meiosis II forms the second polar body and the actual egg containing most of the cytoplasm (Klug, 2012).

Furthermore, oogenesis is not a continuous process but interrupted by a long arrest stage.

During embryogenesis of females oocytes undergo prophase I and arrest in diplonema. This phase of cellular quiescence is called dictyate arrest and lasts at least until puberty. Upon hormone stimulation one or few oocytes exit from the arrest, undergo meiosis until metaphase II and differentiate into a fertilizable eggs. Meiosis II is only completed upon fertilization (Klug, 2012). The later in life of a female an egg is released by ovulation the longer it has been arrested in prophase I.

1.4.2. Pairing of the homologous chromosomes and the synaptonemal complex

Recombination events between homologous chromosomes in meiosis increase genetic diversity since it creates chromosomes that contain a mix of paternal and maternal alleles. In addition, recombination facilitates the pairing of the homologs. The programmed DNA double strand breaks (DSB) are induced in leptonema by the topoisomerase-like protein Spo11 and in its absence the alignment of the homologs is severely inhibited (Zickler and Kleckner, 2015).

Introduction

cells this DNA-protein complex invades the undamaged sister chromatid during the process of repair and pairs with the complementary sequence. The current model suggests that strand exchange between homologous chromosomes and not between sister chromatids in prophase I facilitates pairing of the homologs. Usually the invading strand returns to where it came from after it was extended by DNA synthesis using the complementary sequence of the homolog. However, some of the lesions are repaired in a way that creates lasting interhomolog connections, so called crossovers. The outcome is that one sister chromatid of the parental homolog is ligated to one sister of the maternal homolog (Figure 6). The cohesin rings embracing the sister chromatids distal form the crossover, hence, also tether the homologous chromosomes together (Zickler and Kleckner, 1999, 2015).

In leptonema the chromosomes consist of chromatin loops emanating from a basis formed by proteins that are later part of the SC and called the axial element (AE). After the homologs have aligned along their AEs the distance between the homologs decreases in zygonema in a process called synapsis. Synapsis coincides with the formation of the SC between the homologs. The two AEs of the homologs get connected by transverse filaments consisting of dimers of a large coiled-coil protein. Along these transverse filaments additional proteins accumulate forming the central element. When integrated in the SC the AEs are termed lateral elements. At the end of pachynema the repair of the DSBs is finished and the SC is disassembled. In diplonema the distance between the homologs increases and the chiasmata resulting from crossover events become visible (Figure 6) (Morgan, 2007; Zickler and Kleckner, 1999, 2015).