Regulation of synapsis and crossover formation in C. elegans meiosis

• Applicant: Dr. Simone Köhler
• Subject Area: Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452616889

Meiosis is a specialized cell division process that requires that homologous chromosomes are segregated during meiosis I. To ensure accurate segregation, homologs must first recognize each other, or pair. Pairing is then extended and stabilized by the formation of a proteinaceous structure, the synaptonemal complex that assembles between homologous chromosomes. In addition to stabilizing pairing, the synaptonemal complex enables and regulates the number and distribution of crossover recombination events. These recombination events establish physical linkages between homologous chromosomes that guarantee accurate segregation during meiosis I and give rise to new combinations of genetic traits in future generations. However, despite their importance for the success of meiosis little is known about the mechanisms governing synaptonemal complex assembly and its role in crossover regulation.Using single molecule localization microscopy, I have previously demonstrated that the synaptonemal complex is structurally reorganized upon crossover formation in C. elegans, which suggests that conformational changes underlie the role of the synaptonemal complex in the surveillance of crossover number and localization. I was able to identify a unique mutation in the C-terminus of one of the proteins of the synaptonemal complex, SYP-4, which gives rise to defects in the molecular organization of the synaptonemal complex and disrupts the regulation of crossover formation resulting in a drastic increase in crossover recombination events. By contrast, a different mutation within the C-terminus of SYP-4 interferes with synaptonemal complex formation per se. Together, these data suggest that the C-terminus of SYP-4 plays a central role in regulating the critical steps during meiotic prophase that govern homologous chromosome interactions.Here, I propose to analyze how SYP-4 controls synapsis and crossover formation in meiotic prophase. Given the nature of the mutations in syp-4 I have isolated so far, I hypothesize that SYP-4 is post-translationally modified in vivo to accomplish its diverse tasks. I will test this hypothesis by a combination of biochemical analyses and targeted mutagenesis to dissect the molecular mechanisms of SYP-4's function during meiosis. To analyze how SYP-4 and the synaptonemal complex regulate crossover formation, I will ask how the information about crossover formation is transmitted along individual pairs of chromosomes in vivo. Building on my findings that structural changes within the synaptonemal complex occur upon crossover formation, I will develop sensors to visualize changes in the state of the synaptonemal complex upon crossover formation in real time in vivo. The proposed project will enable me to gain unique insights into the molecular mechanisms of synapsis and crossover regulation, which are the key processes in meiosis and essential for the accurate segregation of homologous chromosomes.

• DFG Programme: Research Grants