UC Berkeley

Meiosis is the specialized cell division by which sexually reproducing organisms produce haploid gametes. In order to reduce the chromosome complement by half, chromosomes must undergo pairing, synapsis, and crossover formation, followed by two rounds of chromosome division. All of these mechanisms depend on the proper establishment, maintenance, and remodeling of sister chromatid cohesion. Sister chromatid cohesion is mediated by cohesin complexes, which associate with newly replicated sister chromatids. Cohesion is required for all major aspects of meiosis: formation of the synaptonemal complex, induction of DNA double-strand breaks, and the repair of breaks to form crossovers, in addition to the regulated release of cohesion to enable segregation. During meiosis, cohesin complexes incorporate specialized subunits and are subject to different regulation, compared to mitotically dividing cells. The functions and regulation of cohesion during meiosis remain poorly characterized, and a major goal of my thesis work has been to address these important questions.

Wapl is a widely conserved regulator of cohesin. It has been implicated in antagonizing the association of cohesin complexes with DNA to facilitate cohesin removal during mitosis. However, its role in meiotic chromosome dynamics has not been investigated in any detail. To better understand the roles and regulation of sister chromatid cohesion in meiosis, I have focused on the Caenorhabditis elegans Wapl homolog, WAPL-1. I found that C. elegans WAPL-1 promotes faithful mitotic chromosome segregation, as in other organisms. I also found that WAPL-1 affects cohesin dynamics during meiosis, contributes to DNA double-strand break repair, and is regulated by the meiosis-specific kinase, CHK-2.

A second component of my thesis work examines the behavior of achiasmate chromosomes during meiosis. When early meiotic events fail to establish the requisite crossovers, the resulting achiasmate chromosomes often missegregate, or nondisjoin. Chromosome nondisjunction can result in aneuploid gametes, which has disastrous consequences for the developing embryo. To accurately detect autosomal nondisjunction in single embryos, I developed a fragment length polymorphism (FLP) assay. I used this approach to analyze chromosome segregation in oocyte meiosis in wildtype animals at different ages, and in mutants with elevated frequencies of achiasmate chromosomes. I found that nondisjunction occurred asymmetrically, yielding a higher frequency of monosomic than trisomic embryos. I also found evidence that germline apoptosis protects C. elegans hermaphrodites from increased nondisjunction as they age. Together, the results of these studies further illuminate meiotic prophase regulation and achiasmate chromosome segregation.