During meiotic prophase, chromosomes undergo dramatic structural changes: They condense, pair and align with their homologous partners, assemble synaptonemal complexes, undergo recombination, and reorganize again to reveal chiasmata, structures that hold homologs together until anaphase I and direct orientation of linked homolog pairs (bivalents) on the meiosis I spindle. These remarkable events are of central importance to sexually reproducing organisms, since they are required to direct the orderly segregation of homologous chromosomes at meiosis I, the specialized cell division that allows diploid organisms to generate haploid gametes. Failure to execute these events correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans. Our goal is to understand how dynamic reorganization of chromosome structure during meiotic prophase is accomplished, and how chromosome organization contributes to successful segregation of homologous chromosomes, particularly in the context of oocyte meiosis where a functional bipolar spindle is assembled in the absence of centrosomes. We are approaching this problem using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining robust cytological, genetic and molecular approaches in a single experimental system, and in which the events under study are particularly accessible. First, we will use both live and fixed imaging to investigate the early meiotic prophase chromosome dynamics that bring about pairing and synapsis of homologous chromosomes. This work will exploit a novel strategy we developed that uses S-phase incorporation of fluorescent nucleotides to label a single chromosome pair along its entire length in live animals;this strategy both enables live time-lapse imaging of whole- chromosome dynamics during the homolog pairing process and identifies populations of tightly- synchronized germ cells for high resolution time course analyses. We will also investigate the functions of meiotic machinery components that promote and coordinate pairing and synapsis. Second, we will evaluate the dynamic properties of meiotic chromosome structures during later prophase as chromosomes remodel in preparation for the meiotic divisions. We will use several approaches to investigate the mechanisms responsible for generating the highly differentiated features of late prophase bivalent architecture that result in reliable chromosome segregation, including a novel genetic screening strategy. Finally, we will use a combination of live and fixed imaging modalities in combination with genetic experiments to investigate assembly and function of the acentrosomal meiotic spindle. Our experiments will test aspects of a model for spindle assembly and chromosome congression developed based on our recent findings and will investigate the mechanistic roles of molecular components implicated in this process by our previous work.

Public Health Relevance

The proposed research will increase our understanding of the basic mechanisms that promote and ensure the faithful inheritance of chromosomes. The work is highly relevant to human health, as errors in chromosome inheritance are one of the leading causes of miscarriages and birth defects and are also a major factor contributing to the development and progression of cancer. Several components of the plan are highly relevant to understanding how features of chromosome organization contribute to assembly and function of the female meiotic spindle, a process that becomes increasingly error-prone with advanced maternal age.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics C Study Section (MGC)
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Janes, Daniel E
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Woglar, Alexander; Villeneuve, Anne M (2018) Dynamic Architecture of DNA Repair Complexes and the Synaptonemal Complex at Sites of Meiotic Recombination. Cell 173:1678-1691.e16
Pattabiraman, Divya; Roelens, Baptiste; Woglar, Alexander et al. (2017) Meiotic recombination modulates the structure and dynamics of the synaptonemal complex during C. elegans meiosis. PLoS Genet 13:e1006670
Mlynarczyk-Evans, Susanna; Villeneuve, Anne M (2017) Time-Course Analysis of Early Meiotic Prophase Events Informs Mechanisms of Homolog Pairing and Synapsis in Caenorhabditis elegans. Genetics 207:103-114
Wolff, Ian D; Tran, Michael V; Mullen, Timothy J et al. (2016) Assembly of Caenorhabditis elegans acentrosomal spindles occurs without evident microtubule-organizing centers and requires microtubule sorting by KLP-18/kinesin-12 and MESP-1. Mol Biol Cell 27:3122-3131
Gabdank, Idan; Ramakrishnan, Sreejith; Villeneuve, Anne M et al. (2016) A streamlined tethered chromosome conformation capture protocol. BMC Genomics 17:274
Roelens, Baptiste; Schvarzstein, Mara; Villeneuve, Anne M (2015) Manipulation of Karyotype in Caenorhabditis elegans Reveals Multiple Inputs Driving Pairwise Chromosome Synapsis During Meiosis. Genetics 201:1363-79
Schvarzstein, Mara; Pattabiraman, Divya; Libuda, Diana E et al. (2014) DNA helicase HIM-6/BLM both promotes MutS?-dependent crossovers and antagonizes MutS?-independent interhomolog associations during caenorhabditis elegans meiosis. Genetics 198:193-207
Bilgir, Ceyda; Dombecki, Carolyn R; Chen, Peter F et al. (2013) Assembly of the Synaptonemal Complex Is a Highly Temperature-Sensitive Process That Is Supported by PGL-1 During Caenorhabditis elegans Meiosis. G3 (Bethesda) 3:585-595
Mlynarczyk-Evans, Susanna; Roelens, Baptiste; Villeneuve, Anne M (2013) Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis. PLoS Genet 9:e1003963
Schvarzstein, Mara; Pattabiraman, Divya; Bembenek, Joshua N et al. (2013) Meiotic HORMA domain proteins prevent untimely centriole disengagement during Caenorhabditis elegans spermatocyte meiosis. Proc Natl Acad Sci U S A 110:E898-907

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