Sexually reproducing organisms rely on meiosis, a specialized cell division that produces haploid gametes such as sperm and eggs, to restore the genetic content of the zygote through fertilization. Errors in this process lead to the production of offspring with an abnormal number of chromosomes or aneuploidy, and this is a major cause of human miscarriages and birth defects such as Down syndrome. Accurate segregation of chromosomes during meiosis requires that they pair, synapse, and undergo crossover recombination with their homologs. Although genetic studies over the decades have identified a list of proteins that are essential for meiotic processes, it remains largely unknown how these protein machines work together to orchestrate chromosome dynamics. My research program will investigate these fundamental processes by combining biochemical and structural analysis using purified components, with the ability to examine meiosis in the context of highly tractable C. elegans germline. Early in meiosis, chromosomes are dramatically reorganized into arrays of chromatin loops tethered to a proteinaceous axis, and this is essential for all major meiotic events, including pairing, synapsis and recombination. The chromosome axis also provides a key interface for checkpoint signaling that links meiotic chromosome dynamics with cell cycle progression. One major focus of our work is the structure and function of the chromosome axis. The axis is composed of meiotic cohesins and additional meiosis-specific components such as HORMA domain proteins. I have demonstrated that meiotic HORMA domain proteins form hierarchical assemblies through binding of their HORMA domains to cognate peptides within their partners. I now propose to expand and build the entire network of proteins within the chromosome axis by reconstituting meiotic cohesins with the HORMA domain proteins. We will examine their structural organization by electron microscopy and determine their distinct features. This work will reveal the complete view of axis organization and provide insights into how the axis interfaces chromatin and controls meiotic recombination. In parallel, we will delineate the signaling cascades by the two major meiotic kinases, CHK-2 and PLK-2, to establish key regulatory mechanisms that govern homolog pairing, synapsis, and meiotic recombination. We will determine the molecular mechanisms by which the HORMA domain proteins regulate the kinase activity of CHK-2, which I have shown to be a master regulator of meiosis and a molecular target of feedback regulation in C. elegans. We will also determine the mechanisms by which PLK-2 regulates assembly and disassembly of the SC and drives remodeling of the chromosome architecture. Our studies will illuminate the mechanisms underlying meiotic chromosome behavior to a biochemical level and ultimately shed light into how organisms faithfully transmit genetic information from parent to progeny.
Meiosis, a specialized cell division that generates sex cells such as sperm and eggs, is essential for the inheritance of genomes from parent to offspring. Errors in this process lead to the production of cells with an abnormal number of chromosomes or aneuploidy, and this is a major cause of miscarriages and birth defects such as Down syndrome. Our findings from this study will elucidate the molecular mechanisms underlying chromosome inheritance during meiosis and will also have general impact in the fields of cell cycle regulation and cancer.
