During the formation of egg and sperm, the maternally- and paternally-inherited chromosomes exchange genetic material in the process known as meiotic crossover recombination. Crossing over creates a transient, physical connection between the homologs that helps them align at metaphase and segregate to opposite poles. Without crossing over, homologs segregate randomly which can lead to aneuploidy, a condition associated with birth defects and miscarriage. The importance of crossover formation is underscored by the extensive crosstalk between meiotic events that ensures their timely and orderly completion. We recently identified a chromosome-by-chromosome surveillance system that couples crossover formation to timely meiotic progression and to stabilization of the synaptonemal complex (SC), a molecular scaffold that stably juxtaposes homologous chromosomes. The first crossover intermediate activates a systemic signal that both changes the dynamics of the SC on the other chromosomes, making them meta-stable, and also promotes chromosome mobility to potentiate crossover formation. We identified the nuclear membrane protein SUN-1 and the polo-like kinase, PLK-2, as key effectors of these signals. The current proposal expands our characterization of the surveillance system to provide mechanistic insight into these processes. Genetic screens will be used to identify the crossover intermediates that are recognized by the surveillance system and the signaling molecules that communicate this to the progression machinery and SC. Using a combination of biochemical and advanced microscopic approaches, we will dissect out the changes that occur to the SC upon activation of the surveillance system and how this regulates crossover formation. We will also further delineate the roles of SUN-1 and PLK-2 in the surveillance system. These studies will increase our understanding of cellular mechanisms that promote genome stability through the monitoring of crossover intermediates. These studies can provide insight into the etiology of birth defects, recurrent miscarriage, premature ovarian failure and male infertility, opening avenues for diagnosis and therapeutic intervention.
The incorrect separation of chromosomes during the cell divisions of meiosis lead to egg and sperm with the wrong number of chromosomes, resulting in miscarriage or birth defects. The majority of these defects arise from errors during the exchange of genetic material between maternal and paternal chromosomes. Mechanistic insight into events that regulate and monitor meiotic exchanges may inform interventions for infertility and recurrent miscarriage.
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