Anne M. Villeneuve
The long range goal of my research program is to understand the molelcular mechanisms underlying the segregation of homologous chromosomes during meiosis. This crucial process is responsible for ensuring that each gamete will contribute exactly one complete set of chromosomes to the zygote, resulting in regeneration of the original diploid chromosome number in the subsequent generation. Further, the precise partitioning of chromosomes during meiosis is critical for the normal development and viability of the resulting embryo.
In most organisms, pairing and crossing over between homologous chromosomes are required to ensure their proper segregation at the meiosis I division. Despite the fundamental importance of meiosis in sexual reproduction, however, the molecular mechanisms underlying these key meiotic events remain poorly understood. How do homologous chromosomes recognize their appropriate pairing partners? How do they become aligned in a configuration that is productive for the formation of crossovers? How is the number of crossover events regulated to ensure that each chromosome pair will have a crossover? How do crossovers function to ensure disjunction of homologs? My laboratory is addressing such basic mechanistic questions by studying meiosis in the nematode Caenorhabditis elegans, a simple experimental organism that is amenable to a combination of genetic, molecular, and cytological approaches.
The C. elegans system offers many advantages for studies of meiotic chromosome segregation. The germline accounts for more than half the cell nuclei in the adult hermaphrodite, providing an abundant and easily accessible source of meiotic material for cytological analyses, and the chromosomes can be visualized by a wide variety of microscopic methods during all stages of meiosis. Genetic mutants that have defects in meiotic chromosome segregation can be identified in a straightforward manner, making this an excellent system for identifying genes involved in the process. We and others haved described several genetic loci required to achieve the normal number and distribution of crossovers, and our systematic genetic screens for meiotic mutants have identified at least eleven additional genes involved in these or other aspects of meiosis. We have developed a battery of genetic and cytological assays to determine which events in meiosis are defective in these mutants. Further, C. elegans researchers have assembled a remarkable set of molecular resources that facilitate the cloning and molecular analysis of these genes.
C. elegans is also a favorable system for addressing questions about the cis-requirements for homolog pairing. Genetic studies suggest that each of the six C. elegans chromosomes has a specialized chromosomal domain located near one end, termed a "meiotic pairing center", that plays an important role in the pairing process. While there is evidence for analogous pairing centers in other systems, the apparent concentration of pairing center activity to a single region on C. elegans chromosomes should make the C. elegans pairing centers more accessible to functional dissection. We have characterized the genetic properties of the X chromosome pairing center in detail, and have initiated a molecular analysis of the locus.
Thus, a powerful combination of biological characteristics and experimental tools collaborate to make the C. elegans system particularly well-suited for investigating the mechanistic bases of meiotic chromosome behavior. We have taken advantage of these resources to identify both trans- and cis-acting components of the meiotic machinery involved in chromosome pairing and recombination. Our long term goal is to understand how these cis- and trans-acting components function and interact to promote pairing and crossing over between homologous chromosomes, and to ensure their proper disjunction at the meiosis I division.