Research in the Villeneuve lab is aimed at understanding the molecular and cellular mechanisms underlying the faithful inheritance and function of eukaryotic chromosomes. Our primary focus is on elucidating the events required for the orderly segregation of homologous chromosomes during meiosis, the crucial process by which diploid germ cells generate haploid gametes. These events are of central importance to sexually reproducing organisms, since failure to execute them correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans.

Diploid germ cells face several major challenges on the road to reducing their ploidy to generate haploid gametes: 1) Each of their chromosomes must locate, identify and align with its appropriate homologous pairing partner. 2) Chromosomes must acquire a structural organization that will promote the controlled breakage of DNA molecules and then subsequently promote recombinational repair using the homologous chromosome (while inhibiting use of the sister chromatid) as a repair partner to yield interhomolog crossovers. 3) Chromosomes must couple the events of recombination with further structural reorganization during later stages of prophase to yield an organization in which homologs are connected by chiasmata, yet oriented away from each other in a way that promotes their attachment to and ultimate segregation toward opposite poles of the meiosis I spindle. Moreover, the connections afforded by chiasmata must be coupled with a two-step loss of cohesion, such that partial loss of cohesion occurs at meiosis I to permit dissolution of chiasmata and homolog separation while maintaining the connections between sisters required to permit congression and bipolar attachment on the meiosis II spindle. 4) During oocyte meiosis, a bipolar spindle must be assembled and function without the aid of centrosomes, This elaborate set of events must be tightly coordinated to achieve a successful outcome.

Despite the fundamental importance of meiosis in sexual reproduction, the mechanisms underlying many key events remain poorly understood. We are approaching the study of meiosis using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining robust genetic, genomic and cytological approaches in a single experimental system, and in which the events of meiosis are particularly accessible. The germ line accounts for more than half of the cell nuclei in the adult organism, with nuclei in all stages of meiosis present simultaneously in a clear temporal/spatial gradient along the distal-proximal axis of the gonad, so that each gonad represents a complete meiotic time course. These features make it possible to visualize chromosome organization using high-resolution microscopic imaging in the context of intact 3D nuclear architecture, both in the context of normal and experimentally perturbed meiosis.

Major topics under investigation include:


How do chromosomes locate their appropriate pairing partners? What is the nature of homolog recognition? How is recognition coordinated with assembly of the the synaptonemal complex (SC), a highly ordered proteinaceous scaffold that stabilizes homolog association, so that synapsis is restricted to occur only between correct partners?


How does the cell sense (and respond to) a chromosome pair that has not yet undergone a crossover? How does a local event (i.e. a crossover) trigger global changes in structure and function along a whole chromosome pair? How do crossover-triggered changes inhibit the formation of other crossovers?


Given that double-strand DNA breaks (DSBs) are dangerous to genomic integrity, how is their formation and repair coordinated with other features of the meiotic program? How does chromatin state affect competence for DSB formation? How is DSB repair directed to use the homolog rather than the sister chromatid as a repair partner?


How does the chromosome organization established during prophase lead to orderly segregation? How does a bipolar spindle assemble during oocyte meiosis, in the absence of centrosomes? What special mechanisms are employed to ensure inheritance of sex chromosomes?


Whereas proteins directly involved in the DNA events of recombination tend to be well-conserved, components of large-scale meiosis-specific chromosome structures exhibit very low conservation. What are the mechanisms responsible for the extreme divergence of meiotic structural proteins?