Current Research and Scholarly Interests
We investigate mechanisms underlying the faithful inheritance of eukaryotic chromosomes. Our primary focus is on elucidating the events required for 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 errors in meiosis lead 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) Chromosomes must locate, identify and align with their appropriate homologous pairing partners. 2) Chromosomes must acquire a structural organization that will promote controlled breakage of DNA molecules and subsequent recombinational repair using the homologous chromosome as a repair partner to yield interhomolog crossovers. 3) Chromosomes must couple the events of recombination with further structural reorganization 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 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 bipolar attachment on the meiosis II spindle. 4) During oocyte meiosis, a bipolar spindle must be assembled and function without the aid of centrosomes. All of these events must be tightly coordinated to achieve a successful outcome.
Despite the fundamental importance of meiosis, the mechanisms underlying many key events remain poorly understood. We are approaching the study of meiosis using the nematode C. elegans, a simple metazoan that is especially amenable to combining genetic, genomic and cytological approaches in a single 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 worm, with nuclei in all stages of meiosis present simultaneously in a temporal/spatial gradient along the distal-proximal axis of the gonad, so that each gonad represents a complete meiotic time course. These features facilitate visualizing chromosome organization using high-resolution microscopic imaging in the context of intact 3D nuclear architecture.
Topics under investigation include:
HOMOLOGOUS CHROMOSOME PAIRING AND SYNAPSIS:
How do chromosomes locate and recognize their appropriate pairing partners? How is recognition coordinated with assembly of the synaptonemal complex (SC), a highly ordered protein scaffold that stabilizes homolog association, so that synapsis occurs only between correct partners?
How do cells sense a chromosome pair that has not yet undergone a crossover? How does a crossover trigger global changes in structure and function along a whole chromosome pair? How do crossover-triggered changes inhibit other crossovers?
COORDINATING CHROMOSOME STRUCTURE WITH RECOMBINATION:
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 does chromosome organization established during prophase lead to orderly segregation? How does the oocyte assemble a bipolar spindle in the absence of centrosomes? What special mechanisms ensure inheritance of sex chromosomes?
EVOLUTION OF MEIOTIC MACHINERY
What mechanisms are responsible for the rapid divergence of meiotic structural proteins?