Once the germ cells have migrated to the gonad, they can begin meiosis. Meiosis is perhaps the most revolutionary invention of eukaryotes. It is difficult now to appreciate how startling this concept was for biologists at the end of the nineteenth century. The discovery of meiosis signaled the critical breakthrough for the investigation of inheritance. Van Beneden’s 1883 observations that the divisions of germ cells caused the resulting gametes to contain half the diploid number of chromosomes “demonstrated that the chromosomes of the offspring are derived in equal numbers from the nuclei of the two conjugating germ-cells and hence equally from the two parents” (Wilson 1924). All subsequent theories of heredity, including the Sutton-Boveri model that united Mendelism with cell biology, are based on meiosis as the mechanism for sexual reproduction and the transmission of genes from one generation to the next.
Meiosis completes the cycle of life. The body decays and dies; but the gametes formed by meiosis survive the death of their parents and form the next generation. Sexual reproduction, evolutionary variation, and the transmission of traits from one generation to the next all come down to meiosis. So to understand what germ cells do, we must first understand meiosis.
Meiosis is initiated and regulated by signals from the gonad. Seen from the germ cell’s view, the gonads exist to provide the signals that coordinate meiosis, gamete maturation, and eventual release. Once in the gonad, the PGCs continue to divide mitotically, often producing millions of potential gamete precursors. The germ cells of both male and female gonads are then faced with the necessity of reducing their chromosomes from the diploid to the haploid condition. In the haploid condition, each chromosome is represented by only one copy, whereas diploid cells have two copies of each chromosome. These meiotic divisions differ from mitotic divisions in that (1) meiotic cells undergo two cell divisions without an intervening period of DNA replication, and (2) homologous chromosomes (each consisting of two sister chromatids joined at a kinetochore) pair together and recombine genetic material.
After the germ cell’s last mitotic division, a period of DNA synthesis occurs, so that the cell initiating meiosis doubles the amount of DNA in its nucleus. In this state, each chromosome consists of two sister chromatids attached at a common kinetochore. (In other words, the diploid nucleus contains four copies of each chromosome.) Meiosis entails two cell divisions. In the first division (meiosis I), homologous chromosomes (for example, the two copies of chromosome 3 in the diploid cell) come together and are then separated into different cells. Hence the first meiotic division splits two homologous chromosomes between two daughter cells such that each daughter cell has only one copy of each chromosome. But each of the chromosomes has already replicated (i.e., each has two chromatids). The second division (meiosis II) separates the two sister chromatids from each other. Consequently, each of the four cells produced by meiosis has a single (haploid) copy of each chromosome.
The first meiotic division begins with a long prophase, which is subdivided into four stages (Figure 1). During the leptotene (Greek, “thin thread”) stage, the chromatin of the chromatids is stretched out very thinly, and it is not possible to identify individual chromosomes. DNA replication has already occurred, however, and each chromosome consists of two parallel chromatids. At the zygotene (Greek, “yoked threads”) stage, homologous chromosomes pair side by side. This pairing is called synapsis, and it is characteristic of meiosis; such pairing does not occur during mitotic divisions. Although the mechanism whereby each chromosome recognizes its homologue is not known (see Barzel and Kupiec 2008; Takeo et al. 2011), synapsis seems to require the presence of the nuclear envelope and the formation of a proteinaceous ribbon called the synaptonemal complex. In many species, the nuclear envelope probably serves as an attachment site for the prophase chromosomes to bind and thereby reduces the complexity of the search for the other homologous chromosome (Comings 1968; Scherthan 2007; Tsai and McKee 2011). The synaptonemal complex is a ladderlike structure with a central element and two lateral bars (von Wettstein 1984; Yang and Wang 2009). The homologous chromosomes become associated with the two lateral bars, and the chromosomes are thus joined together. The configuration formed by the four chromatids and the synaptonemal complex is referred to as a tetrad or a bivalent.
During the next stage of meiotic prophase, pachytene (Greek, “thick thread”), the chromatids thicken and shorten. Individual chromatids can now be distinguished under the light microscope, and crossing-over may occur. Crossing-over represents an exchange of genetic material whereby genes from one chromatid are exchanged with homologous genes from another. Crossing-over may continue into the next stage, diplotene (Greek, “double threads”). Here, the synaptonemal complex breaks down, and the two homologous chromosomes start to separate. Usually, however, they remain attached at various points called chiasmata, which are thought to represent regions where crossing-over is occurring. The diplotene stage is characterized by a high level of gene transcription. In some species, the chromosomes of both male and female germ cells take on the “lampbrush” appearance characteristic of chromosomes that are actively making RNA).
Metaphase begins with diakinesis (Greek, “moving apart”) of the chromosomes (Figure 1, part B). The nuclear envelope breaks down and the chromosomes migrate to form a metaphase plate. Anaphase of meiosis I does not commence until the chromosomes are properly aligned on the mitotic spindle fibers. This alignment is accomplished by proteins that prevent cyclin B from being degraded until after all the chromosomes are securely fastened to microtubules.
During anaphase I, the homologous chromosomes are separated from each other in an independent fashion. This stage leads to telophase I, during which two daughter cells are formed, each cell containing one partner of each homologous chromosome pair. After a brief interkinesis, the second division of meiosis takes place. During this division, the kinetochore of each chromosome divides during anaphase so that each of the new cells gets one of the two chromatids, the final result being the creation of four haploid cells. Note that meiosis has also reassorted the chromosomes into new groupings. First, each of the four haploid cells has a different assortment of chromosomes. Humans have 23 different chromosome pairs; thus 223 (nearly 10 million) different haploid cells can be formed from the genome of a single person. In addition, the crossing-over that occurs during the pachytene and diplotene stages of prophase during meiosis I further increases genetic diversity and makes the number of potential different gametes incalculably large.
This organization and movement of meiotic chromosomes is choreographed by a ring of cohesin proteins that encircle the sister chromatids. The rings of cohesin protein resist the pulling forces of the spindle microtubules and thereby keep the sister chromatids attached together during the first meiotic division (Figure 2; Haering et al. 2008; Brar et al. 2009). The cohesin proteins also recruit other sets of proteins that help promote pairing between the homologous chromosomes and allows recombination to occur (Pelttari et al. 2001; Villeneuve and Hillers 2001; Sakuno and Watanabe 2009). At second meotic division, the ring of cohesin proteins is cleaved and the kinetochores can separate from each other (Schöckel et al. 2011).
Some animal species consist entirely of females; such species are said to be parthenogenetic (Greek, “virgin birth”). In these species, meiosis is modified such that the resulting gamete is diploid and need not be fertilized to develop. In the fly Drosophila mangabeirai, one of the polar bodies (a meiotic cell having very little cytoplasm) acts as a sperm and “fertilizes” the oocyte after the second meiotic division. In some other insects and in the lizard Cnemidophorus uniparens, the oogonia further double their chromosome number before meiosis, so that the halving of the chromosomes restores the diploid number. The germ cells of the grasshopper Pycnoscelus surinamensis dispense with meiosis altogether, forming diploid ova by two mitotic divisions (Swanson et al. 1981). About 80 species are known to be exclusively parthenogenetic, and several other species have been observed to occasionally produce offspring this way (Booth et al. 2012).
In other species, haploid parthenogenesis is widely used not only as a means of reproduction but also as a mechanism of sex determination. In the Hymenoptera (bees, wasps, and ants), unfertilized haploid eggs develop into males, whereas fertilized eggs are diploid and develop into females. The haploid males are able to produce sperm by abandoning the first meiotic division, thereby forming two sperm cells through second meiosis.
1. Although the terms centromere and kinetochore are often used interchangeably, the kinetochore is the complex protein structure that assembles on a sequence of DNA known as the centromere.