UC San Diego

Chromosome segregation during meiosis is a two-step process, where homologous chromosomes segregate in the first meiotic division, and sister chromosomes segregate away in the second, thereby reducing ploidy by half. Homolog segregation in the first meiotic division requires that cells utilize a unique homologous recombination pathway to generate specific physical linkages between homologs in the form of chiasmata. Meiotic recombination involves the introduction of double-stranded breaks (DSBs) to the DNA, which are resected and used in a homology search to identify and associate with the homolog. The mechanisms that ensure accurate chromosome segregation during meiosis are important for maintaining genome stability, and errors in these processes have been shown to lead to miscarriages and developmental diseases like down syndrome.

One of the key adaptations eukaryotic cells have evolved to enable this specialized homologous recombination pathway is a protein assembly called the chromosome axis. The chromosome axis, also known as the axial element (AE), is a highly conserved scaffold that assembles between sister chromosomes. The AE physically organizes the chromatin into a linear array of loops, and also provides a platform for recruitment of the recombination machinery and eventual assembly of the synaptonemal complex. Chromosome axis components are highly conserved in different organisms, and include cohesin complexes, meiotic HORMA domain proteins, and foundation axial element proteins. We find the four HORMA domain proteins from C. elegans organize into a hierarchical complex through binding of highly conserved motifs in their C-terminal tails. We show that the different levels of this hierarchy play distinct roles in regulating chromatin organization and the homologous recombination pathway. This work provides a foundation for understanding both initial recruitment and self-assembly of meiotic HORMADs throughout eukaryotes. We also find that the mammalian foundation AE proteins SYCP2 and SYCP3 self-assemble into higher order filaments, establishing a model for their roles in organizing meiotic chromosomes. Finally, we use next-generation sequencing to examine the organization of meiotic chromosomes in highly synchronized spermatocytes in two meiotic prophase stages, identifying both commonalities with somatic cells and distinct features of meiotic chromosome organization. Overall, this work advances our understanding of meiotic chromosome axis architecture and function across eukaryotes.