The characterization of meiosis-specific cohesin component mutations

Meiosis;Cohesin;Infertility;Genetics;Mouse;Spermatogenesis;Reproductive Biology;not listed

Ward, Ayobami L.

Johns Hopkins University

关键词: Meiosis;    Cohesin;    Infertility;    Genetics;    Mouse;    Spermatogenesis;    Reproductive Biology;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/44603/2015%20JUN%2024%20FINAL%20THESIS.docx?sequence=2&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Cohesin is an essential structural component of chromosomes that ensures accurate chromosome segregation during mitosis and meiosis. Cohesin mutations result in a range of disorders including developmental defects, cancer and infertility, and are collectively termed ;;Cohesinopathies”. Previous studies have shown that there are cohesin complexes specific to meiosis, required to mediate homologous chromosome pairing, recombination and segregation. The meiosis-specific cohesin complexes consist of two Structural Maintenance of Chromosomes (SMC1α/SMC1β and SMC3) proteins, an α-kleisin protein (RAD21, RAD21L or REC8), and a stromal antigen protein (STAG3). STAG3 is a component of all meiotic cohesin complexes, interacting directly with each α-kleisin subunit. Together, these cohesins provide stability to the tripartite structure known as the Synaptonemal Complex (SC), which provides a scaffold that ensures homologous chromosomes pair and recombine during meiosis. Our lab recently reported that germ cells from Stag3 mutant mice arrest in early prophase (;;zygotene-like” stage), due to failed homolog synapsis, impaired centromeric cohesion and defective DNA damage responses. These defects are due to meiotic cohesin instability, resulting in unstable binding to the SC. Mouse mutants for meiosis-specific α-kleisin subunits Rad21l and Rec8 exhibited phenotypically distinct zygotene-like arrests that are less severe than those observed in the Stag3 mutant. However, Rec8, Rad21L double mutants resulted in a more severe ;;leptotene-like” arrest accompanied by complete absence of STAG3 loading onto chromosome axes. Therefore, we hypothesized that STAG3 is required for the stability and not the initial axis loading of REC8 and RAD21L containing cohesins.To assess interactions between STAG3 and α-kleisin subunits RAD21L and REC8, our lab has generated Stag3/Rad21L and Stag3/Rec8 double knockout mice. As hypothesized, these two mutants are phenotypically distinct from one another and more severe than each single knockout mutant. Stag3/Rad21L and Stag3/Rec8 double mutants exhibit further meiotic progression than the previously described Rec8, Rad21L double mutants. Our genetic analysis further demonstrates that STAG3 is necessary to stabilize meiosis-specific cohesins to the SC.