Roles of Cohesins SMC3, RAD21 and STAG3 in Mammalian Meiosis

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Why are there meiosis-specific cohesin proteins, which roles do the various cohesin complexes play in male and female meiosis, which functions do “ubiquitous” cohesins contribute to meiocytes? Currently, none of these questions can be satisfactorily answered, and yet it is clear that cohesins play essential roles in gametogenesis, in meiosis. In meiosis, cohesins determine the chromosomal architecture, promote synapsis and recombination, are required for sister chromatid cohesion, proper segregation of chromosomes, and protect telomere integrity. Thus, they are key to reproductive health.Our overall hypothesis is that in male and female meiocytes several specific cohesin complexes act at specific stages and serve specific functions, which are however too little understood. We will address some of the central questions related to this biologically fundamental problem. Based on specific hypotheses concerning the individual cohesin subunits as outlined in the main section, our immediate specific aims are:(1) To understand the meiotic functions and properties of cohesins SMC3 and RAD21(2) To determine protein associations of the meiosis-specific cohesin STAG3The evolutionarily highly conserved SMC3 and RAD21 are components of somatic and meiotic cohesin complexes, form dynamically and stably chromosome-associated cohesin pools as we recently observed in meiocytes, and are either subunit of all (SMC3) or selected (RAD21) cohesin complexes in meiosis. However, despite clear indications for important and specific meiotic functions, their meiotic roles were not described and will now be assessed. STAG3 is the only meiosis-specific STAG-type cohesin, and we hypothesize that in meiocytes it acts as platform for interactions of cohesin with other proteins, which shall now be characterized. STAG3’s deletion shows the most dramatic chromosomal phenotype of all single meiotic cohesin deficiencies tested so far. We have assembled the probably most comprehensive set of tools in the field of mammalian meiotic cohesin research, including a large variety of sophisticated mouse strains, to address these questions. We expect to contribute significantly to our understanding of cohesin proteins central in mammalian meiosis and thus key to reproductive health, i.e. their roles in spermatocyte and oocyte chromosome dynamics and their molecular properties.