Investigating the Molecular Architecture of the Synaptonemal Complex and its Role in Crossover Formation.

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Project Summary In sexually reproducing organisms, inheritance of a stable genome relies on meiosis, a specialized cell division that produces haploid gametes from a diploid cell. Defects in this process lead to abnormal chromosome numbers, also known as aneuploidy, and this is a major cause of infertility and developmental disorders such as Down Syndrome. Successful segregation of chromosomes during meiosis requires that homologs pair, synapse, and form crossovers. The process of synapsis is defined by the formation of a proteinaceous structure called the synaptonemal complex (SC), which links two homologs together and serves as a scaffold for crossover recombination. The SC consists of two parallel stretches of chromatin-associated axial elements and a central region comprised of transverse elements, which connect homologs in a zipper-like fashion. Despite its structural conservation across most eukaryotes, little is known about the mechanisms governing SC assembly and its functions. The goal of this proposal is to determine the structure and functions of the SC using the nematode C. elegans as a model organism. The transverse elements in C. elegans are comprised of at least four coiled-coil proteins, SYP-1, SYP-2, SYP-3, and SYP-4, which are interdependent for their assembly. I have recently discovered two new components of the SC, SYP-5 and SYP-6, which are paralogous to each other and play redundant roles in synapsis. In Aim 1, I will extend these findings and determine the significance of highly conserved disordered C-termini of SYP-5/6. Recent evidence in C. elegans suggests that the SC has liquid-like properties, thereby enabling long-range signal transduction to mediate a chromosome-wide crossover control. I will examine whether the C-terminal tails of SYP-5/6 contribute to this dynamic behavior of the SC and crossover regulation. In Aim 2, I will determine the biochemical characteristics of the SC using the SYP protein complexes purified from C. elegans as well as the recombinant proteins. I will determine the stoichiometry and protein- protein interactions among the SC components and determine their propensity and requirements to form polymers or liquid-like droplets. Overall, this work will provide key insights into the fundamental principles of SC organization and its functions, which will be broadly applied across species, including humans. Through the work proposed in this application, I will learn key experimental skills in genetics, cell biology, and protein biochemistry. Combined with the state-of-the-art research environment, excellent training faculty, and career development programs, Johns Hopkins University is an ideal place to foster my development into an independent scientist.