Meiosis is the basis for practically all of eukaryotic genetics on this planet but our molecular understanding of this form of cell division is poor in comparison to our knowledge about the mitotic cell cycle. A detailed molecular understanding of meiosis is of obvious medical and social relevance.
Errors in meiotic chromosome segregation are the leading causes for infertility, premature pregnancy loss, and mental retardation in humans. In a simplified view, chromosome segregation is controlled by a biochemical network that consists of two closely interconnected levels: a set of largely soluble kinases and ubiquitin ligases forms a molecular pacemaker, which controls the activities of chromatin-associated protein complexes that determine, in turn, the interaction, shape, and movement of chromosomes. Meiosis is much more intricate than mitosis because it consists of two nuclear divisions: meiosis I, where homologous chromosomes segregate, and meiosis II, where sister chromatids disjoin (as in mitosis). Thus, the meiotic control system has to be able to regulate two chromosome segregation events with different and often mutually exclusive requirements. To ensure the production of viable gametes, the control system has to promote first the reductional (in meiosis I) and then the equational (in meiosis II) mode of chromosome segregation but never both at the same time. In other words, the system has to frequently “decide” between two options. Our aim is to understand how these decisions are generated and how they are ordered into the sequence that generates haploid gametes and that we call meiosis.
We study meiosis in budding yeast because it offers a combination of classical genetics and genome manipulation with single-nucleotide precision. However, rapid progress has been hampered until recently by the lack of several basic technologies. Thus, we have developed methods to induce meiosis in large-scale cultures and to purify protein complexes suitable for mass spectrometric analysis and biochemical in vitro reconstitution. To improve the poor synchrony of meiotic cultures, we have developed arrest/releases systems that generate extremely high synchrony, comparable to that achieved in mitotic cell cycle experiments. Finally, we have established live-cell imaging and quantitative analysis of the entire meiotic program in budding yeast. To address the question of evolutionary conservation, we analyze meiosis also in fission yeast. The aim of our work in yeast is to generate working hypotheses relevant to the regulation of meiosis in mammals including humans.