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Priority Programme 1384: “Mechanisms of Genome Haploidization”
There is no other cell as important as the germ cell! This rather provocative but largely correct statement illustrates the central role germ cells play in biology and medicine. No higher organisms without germ cells, no evolution of higher organisms without germ cells, no faithful inheritance of genomes without germ cells and – at least in mammals and many other species – without the central process of meiosis, i.e. genome haploidization.
Sterility syndromes and aneuploidy syndromes such as the Down Syndrome – both frequent and very serious medical problems – appear when genome haploidization goes awry. Yet, genome haploidization and the underlying molecular and cellular events are poorly understood. This is particularly true if compared to our understanding of somatic cell development and of mitosis. One reason is the complexity of male and female meiotic processes, which are difficult to study. The recent advent of new techniques and the combination of different experimental systems – from yeast to mice – render genome haploidization more amenable to functional, mechanistic, molecular and cellular research than ever before.

During cell division each chromosome must be faithfully duplicated into two sister chromatids, which must then be properly segregated to generate daughter cells with a genome of high integrity and of the same ploidy as that of the parent cell. There is one exception critical for reproductive life and for human health: genome haploidization to produce functional germ cells. Just prior to meiosis, the genome is duplicated but then during meiosis in two subsequent divisions steps reduced to haploidy. Despite the obvious importance of the process of genome haploidization, without which no germ cells could be generated in man, in most other vertebrates, and in most lower eukaryotes, we understand very little about its mechanics, its regulation, and the key factors that drive genome haploidization.

Genome haploidization requires unique molecular and cellular processes, which are fundamentally different from events in mitosis (Fig. 1). Two rounds of chromosome segregation in the absence of DNA replication, a unique chromosome structure with paired and compacted homologues within a specific protein-DNA structure called the synaptonemal complex, an obligatory interhomolog recombination reaction with chiasmata formation, telomere attachment to the nuclear periphery and telomere bouquet formation, the very long and potentially dangerous dictyate arrest of oocytes, and the segregation of homologs instead of sister chromatids in meiosis I are among the essential elements of genome haploidization. The specific requirements of genome haploidization are consequently reflected in a substantial number of proteins, which are only expressed during this process and/or perform meiosis-specific functions. Many of these functions and the rather complex processes mentioned above and below need to be intensely researched.

general_scheme_of_meiosis.png

General scheme of meiosis


Genome haploidization starts after the last premeiotic replication and thus with four sister chromatids, each two joined together to form a so-called homolog or univalent. The two univalents then pair to form the bivalent, which is packed into a proteinaceous structure called the synaptonemal complex (SC). How homolog pairing and assembly of the SC are regulated and the functionof the SC is not sufficiently understood.

pachytene_spermatocytes.pngPachytene spermatocytes, with SCs (green), telomeres (red), and chromatin (DAPI, blue) stained.


Two rounds of chromosome segregation, meiosis I and II, ensure that four haploid gametes (or polar bodies) are produced, each containing one of the sister chromatids. In the first division, the homologs, i.e. the two pairs of sister chromatids, separate and the sister chromatids stay together in cohesion, linked at their centromeres. In meiosis II, centromeric cohesion is dissolved and individual sister chromatids are segregated. Thus, meiosis II is very similar to mitotic division, while meiosis I is highly specific and requires unique chromosome structures, behaviour, spindle function, anf other mechanisms.  For example, unlike in mitosis where kinetochores on the sister chromatids attach to spindle microtubules originating from opposite poles (bipolar attachment), in meiosis I sister chromatid kinetochores attach to the microtubules from the same pole (monopolar attachment). The mechanisms governing monopolar versus bipolar attachment need to be investigated. Formation of at least one chiasma per chromosome, the structural manifestation of sites of recombination between homologs but not between sister chromatids, is required to properly align the bivalent with its two homologs on the metaphase plate. Many unsolved questions surround meiotic recombination, chiasma formation and resolution, but also checkpoint features, meiotic DNA repair, and regulation of transcription from meiotic chromosomes.

oocyte_chromosomes.pngOocyte chromosomes with sites of recombination (left; SC red; MLH1 foci green) and chiasmata (right) visualized.


Meiotic chromosomes undergo unusual movements like the attachment of their telomeric ends at the nuclear envelope, their subsequent clustering on one spot on the inner membrane, and subsequent dissociation from the envelope. The function of such movements, like the role of oscillations of the nucleus and its communication with the surrounding cytoplasm remain mostly mysterious.

Thus, to fully understand genome haploidization one needs to understand how it is initiated, carried through and terminated. Therefore, this DFG Priority Program calls for the participation of groups that study factors and processes required for the initiation of meiosis, the most critical steps of genome haploidization itself and its completion. To maintain the focus on genome haploidization, we do not include loosely related research areas such as development of germ cells from embryonic stem cells, primordial germ cell migration, or fertilization as we feel that these topics are either covered by other programs or would significantly dilute the scientific focus of this program.