Chromosomal Control of Segregation of C. Elegans

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): Sexual reproduction involves the fusion of two sets of chromosomes - one from each parent - to form a new zygote. To avoid doubling their chromosome number with each successive generation, all sexually reproducing organisms must undergo meiosis. This special cell division gives rise to haploid gametes such as sperm, eggs, and pollen, which contain one complete set of chromosomes. Errors in meiosis are a major cause of human miscarriages, infertility, and chromosomal birth defects such as Down syndrome. The defining event of meiosis is a reductional division, in which the two homologous copies of each chromosome are segregated to different daughter cells. To accomplish this separation, each chromosome must first establish a physical connection with its partner through pairing, assembly of the synaptonemal complex, and recombination. The overall goal of this project is to understand the mechanisms that orchestrate these chromosome interactions and ensure that they occur faithfully. We study meiosis in the nematode worm C. elegans, which offers major experimental advantages, including outstanding cytology and powerful genetic tools. Recent technical breakthroughs have made it possible to engineer transgenes that are expressed reliably in meiotic cells. Consequently, we now have an opportunity to address questions about meiotic mechanisms in fundamentally new ways. The work proposed here harnesses these new methods to accomplish two major goals: 1) define the roles of six conserved cell cycle kinases in meiotic progression, and 2) investigate the dynamics of synaptonemal complex assembly. The major families of kinases that regulate mitotic cell cycles are also involved in meiotic progression, and almost certainly play critical roles in chromosome pairing, synapsis, and recombination. However, because many of these enzymes are required for viability and development, it has been difficult to study their specific meiotic functions in animal models. Here we will take advantage of chemical genetic techniques, which make it possible to inhibit a kinase of interest rapidly and specifically in a living animal, to study the roles of a selected group of kinases during meiosis. In parallel, we will identify direct targets for these kinases and study the consequences of their phosphorylation in vivo. Our other major goal is to study the dynamic process of synaptonemal complex assembly through direct in vivo imaging and image analysis. To accomplish this, we will first engineer fluorescent reporters to mark structural components of the synaptonemal complex. Using in vivo imaging, image analysis, and mathematical modeling, we will learn how this molecular machine assembles from its component parts to regulate chromosome interactions during meiosis.