Interplay between Synaptonemal Complex, Homologous Recombination, and Centromeres during Mammalian Meiosis

Abstract

The intimate synapsis of homologous chromosome pairs (homologs) by synaptonemal complexes (SCs) is an essential feature of meiosis. In many organisms, synapsis and homologous recombination are interdependent: recombination promotes SC formation and SCs are required for crossing-over. Moreover, several studies indicate that initiation of SC assembly occurs at sites where crossovers will subsequently form. However, recent analyses in budding yeast and fruit fly imply a special role for centromeres in the initiation of SC formation. In addition, in budding yeast, persistent SC–dependent centromere-association facilitates the disjunction of chromosomes that have failed to become connected by crossovers. Here, we examine the interplay between SCs, recombination, and centromeres in a mammal. In mouse spermatocytes, centromeres do not serve as SC initiation sites and are invariably the last regions to synapse. However, centromeres are refractory to de-synapsis during diplonema and remain associated by short SC fragments. Since SC–dependent centromere association is lost before diakinesis, a direct role in homolog segregation seems unlikely. However, post–SC disassembly, we find evidence of inter-centromeric connections that could play a more direct role in promoting homolog biorientation and disjunction. A second class of persistent SC fragments is shown to be crossover-dependent. Super-resolution structured-illumination microscopy (SIM) reveals that these structures initially connect separate homolog axes and progressively diminish as chiasmata form. Thus, DNA crossing-over (which occurs during pachynema) and axis remodeling appear to be temporally distinct aspects of chiasma formation. SIM analysis of the synapsis and crossover-defective mutant Sycp1 ^−/− implies that SCs prevent unregulated fusion of homolog axes. We propose that SC fragments retained during diplonema stabilize nascent bivalents and help orchestrate local chromosome reorganization that promotes centromere and chiasma function.

Author Summary

Gamete cells, such as sperm and eggs, form via the specialized cell division called meiosis. Essential and interdependent features of meiosis include the pairing, recombination, and segregation of maternal and paternal chromosomes. Chromosome pairing culminates with formation of synaptonemal complexes (SCs), zipper-like structures that connect the structural cores or axes of homologous chromosomes. Although SC is known to be important for crossover recombination, details of its function remain enigmatic. In this study, we analyze mouse spermatocytes to investigate the interplay between SC, recombination, and centromeres (the structures that direct chromosome segregation). We show that SC prevents unregulated interactions between chromosome axes. This function appears to be especially important at chromosome ends and at crossover sites where DNA exchange must be coordinated with structural exchange of chromosome axes. We also show that centromeres remain associated by short fragments of SC after general chromosome desynapsis has occurred. Furthermore, we detect a distinct type of inter-centromeric connection that persists even after centromeres desynapse. Such connections may facilitate the segregation of chromosomes that have failed to crossover. Together, our data provide new insights into the functions of SC and raise the possibility of a back-up chromosome segregation system in mammals analogous to those described in fruit flies and budding yeast.