Chromosomal birth defects and age-related infertility in humans arise from errors in meiosis, the specialized cell division process required for sexual reproduction. During meiosis, the maternal and paternal copies of each chromosome pair with each other and undergo crossover recombination. This process leads to the formation of physical links between partner chromosomes and directs their segregation to different daughter cells. Studies of human aneuploidy and experiments in model organisms have demonstrated that errors frequently arise when crossovers either fail to occur between partner chromosomes, or occur at suboptimal positions along the chromosomes. The mechanisms that govern chromosome-wide crossover number and placement, sometimes referred to as ?crossover control,? remain poorly understood. In most organisms, crossovers between each pair of homologous chromosomes are required for proper segregation. Mechanisms known as ?crossover assurance? and ?crossover interference? ensure that each chromosome pair undergoes a crossover while strictly limiting the total number of crossovers. This has implied the existence of chromosome-wide signals that mediate crossover control. The nature of these signals has been enigmatic and highly controversial. Recent work in my lab has illuminated a novel signaling circuit that regulates crossovers in C. elegans. Our published work and preliminary findings reveal that this circuit acts within a unique polymer, the synaptonemal complex, which forms a phase-separated compartment between homologous chromosomes. The work proposed here will expand our understanding of this circuit and the mechanisms by which key regulatory factors are confined within this compartment. Through this work we will illuminate widely conserved mechanisms governing meiotic recombination and will also explore how a cellular switch- like signal can be spatially confined within a non-membrane-bound cellular compartment, a principle that is likely to impact diverse cell biological pathways.

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Chromosomal birth defects and infertility in humans often arise through errors in meiosis, the specialized cell division process required for sexual reproduction. We will investigate the regulatory circuitry that regulates the formation of crossovers during meiosis to ensure accurate chromosome segregation. This work will illuminate how regulatory signals can be spatially confined within cells and advance our understanding of widely-conserved mechanisms governing genome stability and inheritance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Keane-Myers, Andrea
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University of California Berkeley
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Zhang, Liangyu; Köhler, Simone; Rillo-Bohn, Regina et al. (2018) A compartmentalized signaling network mediates crossover control in meiosis. Elife 7:
Rog, Ofer; Köhler, Simone; Dernburg, Abby F (2017) The synaptonemal complex has liquid crystalline properties and spatially regulates meiotic recombination factors. Elife 6:
Köhler, Simone; Wojcik, Michal; Xu, Ke et al. (2017) Superresolution microscopy reveals the three-dimensional organization of meiotic chromosome axes in intact Caenorhabditis elegans tissue. Proc Natl Acad Sci U S A 114:E4734-E4743
Yu, Zhouliang; Kim, Yumi; Dernburg, Abby F (2016) Meiotic recombination and the crossover assurance checkpoint in Caenorhabditis elegans. Semin Cell Dev Biol 54:106-16
Rog, Ofer; Dernburg, Abby F (2015) Direct Visualization Reveals Kinetics of Meiotic Chromosome Synapsis. Cell Rep :
Kim, Yumi; Kostow, Nora; Dernburg, Abby F (2015) The Chromosome Axis Mediates Feedback Control of CHK-2 to Ensure Crossover Formation in C. elegans. Dev Cell 35:247-61
Zhang, Liangyu; Ward, Jordan D; Cheng, Ze et al. (2015) The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C. elegans. Development 142:4374-84
Kim, Yumi; Rosenberg, Scott C; Kugel, Christine L et al. (2014) The chromosome axis controls meiotic events through a hierarchical assembly of HORMA domain proteins. Dev Cell 31:487-502
Rog, Ofer; Dernburg, Abby F (2013) Chromosome pairing and synapsis during Caenorhabditis elegans meiosis. Curr Opin Cell Biol 25:349-56
Stamper, Ericca L; Rodenbusch, Stacia E; Rosu, Simona et al. (2013) Identification of DSB-1, a protein required for initiation of meiotic recombination in Caenorhabditis elegans, illuminates a crossover assurance checkpoint. PLoS Genet 9:e1003679

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