Meiotic Chromosome Segregation in C. elegans

Summary

Principal Investigator: Anne Villeneuve
Affiliation: Stanford University
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 1996-02-08 - 2013-01-13
more information: NIH RePORT

Top Publications

  1. pmc HTP-1-dependent constraints coordinate homolog pairing and synapsis and promote chiasma formation during C. elegans meiosis
    Enrique Martinez-Perez
    Department of Developmental Biology, Stanford University School of Medicine, California 94305, USA
    Genes Dev 19:2727-43. 2005
  2. pmc Coordinating cohesion, co-orientation, and congression during meiosis: lessons from holocentric chromosomes
    Mara Schvarzstein
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    Genes Dev 24:219-28. 2010
  3. pmc Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis
    Susanna Mlynarczyk-Evans
    Departments of Developmental Biology and Genetics, Stanford University School of Medicine, Stanford, California, United States of America
    PLoS Genet 9:e1003963. 2013
  4. pmc Chromosome movements promoted by the mitochondrial protein SPD-3 are required for homology search during Caenorhabditis elegans meiosis
    Leticia Labrador
    MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, London, United Kingdom
    PLoS Genet 9:e1003497. 2013
  5. pmc Meiotic HORMA domain proteins prevent untimely centriole disengagement during Caenorhabditis elegans spermatocyte meiosis
    Mara Schvarzstein
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 110:E898-907. 2013
  6. pmc HAL-2 promotes homologous pairing during Caenorhabditis elegans meiosis by antagonizing inhibitory effects of synaptonemal complex precursors
    Weibin Zhang
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America
    PLoS Genet 8:e1002880. 2012
  7. pmc Chromosome painting reveals asynaptic full alignment of homologs and HIM-8-dependent remodeling of X chromosome territories during Caenorhabditis elegans meiosis
    Kentaro Nabeshima
    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor Michigan, USA
    PLoS Genet 7:e1002231. 2011
  8. pmc The synaptonemal complex shapes the crossover landscape through cooperative assembly, crossover promotion and crossover inhibition during Caenorhabditis elegans meiosis
    Michiko Hayashi
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    Genetics 186:45-58. 2010
  9. pmc A Caenorhabditis elegans RNA-directed RNA polymerase in sperm development and endogenous RNA interference
    Jonathan I Gent
    Department Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
    Genetics 183:1297-314. 2009
  10. pmc Lateral microtubule bundles promote chromosome alignment during acentrosomal oocyte meiosis
    Sarah M Wignall
    Department of Developmental Biology, Stanford University School of Medicine, CA 94305, USA
    Nat Cell Biol 11:839-44. 2009

Scientific Experts

  • Sarah M Wignall
  • Anne M Villeneuve
  • Kentaro Nabeshima
  • Enrique Martinez-Perez
  • Mara Schvarzstein
  • Susanna Mlynarczyk-Evans
  • Sarit Smolikov
  • Amy J MacQueen
  • Leticia Labrador
  • Weibin Zhang
  • Michiko Hayashi
  • Jonathan I Gent
  • MONICA P COLAIACOVO
  • Andreas Eizinger
  • Aimee Jaramillo-Lambert
  • JoAnne Engebrecht
  • Allison Hurlburt
  • Divya Pattabiraman
  • James Lightfoot
  • Jon Taylor
  • Stephane Flibotte
  • Consuelo Barroso
  • JOSHUA N BEMBENEK
  • Baptiste Roelens
  • Donald G Moerman
  • Thomas Müller-Reichert
  • Natasha Miley
  • Aya Sato
  • Peter M Carlton
  • Michael S Zastrow
  • Sam Guoping Gu
  • Verena Jantsch
  • Antoine Baudrimont
  • Andrew Z Fire
  • Eric Rogers
  • Kent McDonald
  • Marina Ellefson
  • Kristina Schild-Prufert
  • Pinky Weiser
  • Carolyn M Phillips
  • Needhi Bhalla
  • Abby F Dernburg

Detail Information

Publications16

  1. pmc HTP-1-dependent constraints coordinate homolog pairing and synapsis and promote chiasma formation during C. elegans meiosis
    Enrique Martinez-Perez
    Department of Developmental Biology, Stanford University School of Medicine, California 94305, USA
    Genes Dev 19:2727-43. 2005
    ..We propose a model in which HTP-1 functions to establish or maintain multiple constraints that operate to ensure coordination of events leading to chiasma formation...
  2. pmc Coordinating cohesion, co-orientation, and congression during meiosis: lessons from holocentric chromosomes
    Mara Schvarzstein
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    Genes Dev 24:219-28. 2010
    ..Finally, we illustrate how analysis of holocentric meiosis can inform our thinking about mechanisms that operate on monocentric chromosomes...
  3. pmc Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis
    Susanna Mlynarczyk-Evans
    Departments of Developmental Biology and Genetics, Stanford University School of Medicine, Stanford, California, United States of America
    PLoS Genet 9:e1003963. 2013
    ....
  4. pmc Chromosome movements promoted by the mitochondrial protein SPD-3 are required for homology search during Caenorhabditis elegans meiosis
    Leticia Labrador
    MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, London, United Kingdom
    PLoS Genet 9:e1003497. 2013
    ....
  5. pmc Meiotic HORMA domain proteins prevent untimely centriole disengagement during Caenorhabditis elegans spermatocyte meiosis
    Mara Schvarzstein
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 110:E898-907. 2013
    ..elegans also function to inhibit centriole separation at meiosis II, thereby ensuring that the zygote inherits the appropriate complement of chromosomes and centrioles...
  6. pmc HAL-2 promotes homologous pairing during Caenorhabditis elegans meiosis by antagonizing inhibitory effects of synaptonemal complex precursors
    Weibin Zhang
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America
    PLoS Genet 8:e1002880. 2012
    ....
  7. pmc Chromosome painting reveals asynaptic full alignment of homologs and HIM-8-dependent remodeling of X chromosome territories during Caenorhabditis elegans meiosis
    Kentaro Nabeshima
    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor Michigan, USA
    PLoS Genet 7:e1002231. 2011
    ....
  8. pmc The synaptonemal complex shapes the crossover landscape through cooperative assembly, crossover promotion and crossover inhibition during Caenorhabditis elegans meiosis
    Michiko Hayashi
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
    Genetics 186:45-58. 2010
    ....
  9. pmc A Caenorhabditis elegans RNA-directed RNA polymerase in sperm development and endogenous RNA interference
    Jonathan I Gent
    Department Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
    Genetics 183:1297-314. 2009
    ..These and other data suggest a working model in which a major role of the RRF-3/ERI pathway is to generate siRNAs that set patterns of gene expression through feedback repression of a set of critical targets during spermatogenesis...
  10. pmc Lateral microtubule bundles promote chromosome alignment during acentrosomal oocyte meiosis
    Sarah M Wignall
    Department of Developmental Biology, Stanford University School of Medicine, CA 94305, USA
    Nat Cell Biol 11:839-44. 2009
    ....
  11. pmc Crossovers trigger a remodeling of meiotic chromosome axis composition that is linked to two-step loss of sister chromatid cohesion
    Enrique Martinez-Perez
    Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, United Kingdom
    Genes Dev 22:2886-901. 2008
    ..Further, we discuss parallels between the pattern of HTP-1/2 removal in response to crossovers and the phenomenon of crossover interference...
  12. ncbi Differential timing of S phases, X chromosome replication, and meiotic prophase in the C. elegans germ line
    Aimee Jaramillo-Lambert
    Section of Molecular and Cellular Biology, Genetics Graduate Group, University of California, Davis, CA 95616, USA
    Dev Biol 308:206-21. 2007
    ..On the other hand, meiotic prophase for sperm production in males is completed by 20-24 h. Possible sources for the sex-specific differences in meiotic prophase kinetics are discussed...
  13. pmc Synapsis-defective mutants reveal a correlation between chromosome conformation and the mode of double-strand break repair during Caenorhabditis elegans meiosis
    Sarit Smolikov
    Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
    Genetics 176:2027-33. 2007
    ..Moreover, our studies suggest that the conformation of chromosomes may influence the mode of DSB repair employed during meiosis...
  14. pmc SYP-3 restricts synaptonemal complex assembly to bridge paired chromosome axes during meiosis in Caenorhabditis elegans
    Sarit Smolikov
    Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
    Genetics 176:2015-25. 2007
    ..Altogether, our studies lead us to propose that SYP-3 regulates synapsis along chromosomes, contributing to meiotic progression in early prophase...
  15. ncbi Chromosome sites play dual roles to establish homologous synapsis during meiosis in C. elegans
    Amy J MacQueen
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cell 123:1037-50. 2005
    ..We speculate that concentration of these activities at one region per chromosome may have coevolved with the loss of a point centromere to safeguard karyotype stability...
  16. pmc Crossing over is coupled to late meiotic prophase bivalent differentiation through asymmetric disassembly of the SC
    Kentaro Nabeshima
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
    J Cell Biol 168:683-9. 2005
    ..We propose that crossovers or crossover precursors serve as symmetry-breaking events that promote differentiation of subregions of the bivalent by triggering asymmetric disassembly of the SC...