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, the linkages that hold homologs together until anaphase I. These 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 contributes to successful segregation of homologous chromosomes, particularly in the context of oocyte meiosis where the chromosomes are thought to play a central role in nucleating formation of the meiotic spindle. We are approaching this problem using the nematode C. elegans, a simple metazoan organism that is especially amenable to combining robust genetic, genomic and cytological approaches in a single experimental system, and in which the events under study are particularly accessible. We will investigate how features of meiotic chromosome structure generated during meiotic prophase contribute to chromosome and spindle dynamics at the oocyte meiosis I division, using high resolution imaging of both fixed and live specimens and exploiting our collection of meiotic mutants and our ability to manipulate karyotype to alter meiotic chromosome organization. We will use an integrated genetic, cytological, biochemical and proteomics approach to investigate how known meiotic machinery components coordinate homolog pairing and SC assembly to ensure that meiotic structures develop appropriately, linking axes of coaligned homologous chromosomes. We will use tools that monitor the status of pairing in live worms as the basis of screens designed to identify pairing machinery components, as a route toward molecular definition of cis-acting chromosomal features that stabilize pairing, and as a means to perform live imaging of pairing dynamics. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053804-13
Application #
7345414
Study Section
Genetics Study Section (GEN)
Program Officer
Portnoy, Matthew
Project Start
1996-02-08
Project End
2009-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
13
Fiscal Year
2008
Total Cost
$303,229
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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