The specialized cell division of meiosis results in the formation of haploid gametes from diploid precursors allowing for the maintenance of chromosomal copy number to subsequent generations. Central to this process is the process of crossover recombination that promotes the exchange of genetic information between the maternal and paternal chromosomes. Crossing over both increases offspring diversity and creates a physical link between the homologs that ensures their proper segregation during the first meiotic division. In the absence of crossing over, homologs segregate randomly which can lead to aneuploidy. The importance of establishing a crossover is underscored by multiple checkpoint mechanisms ensure the correct timing and order of the events leading up to crossover formation, specifically pairing, synapsis and double strand break formation. In this grant, we explore a novel surveillance system that is activated by a defect in crossover formation on a single chromosome. This leads to a delay in meiotic progression and loss of the synaptonemal complex between non-recombinant homolog pairs. We use the range of molecular, genetic, biochemical and cytological tools available in C. elegans to define and characterize this surveillance system. The three aims of this grant will dissect out the requirements for communication between the crossover, the meiotic progression machinery, and the synaptonemal complex. We will analyze the requirements for activation of the surveillance system by manipulating crossover number using a system to induce meiotic double strand breaks into spo-11 mutants that cannot form them. We will generate a series of double mutant combinations to define and characterize the cis- and trans-acting signals that promote delay and desynapsis. We propose detailed functional analyses of two downstream targets of the signaling cascade: the integral nuclear membrane protein SUN-1 that is required for chromosome interactions with the nuclear periphery;and SYP proteins, the core components of the synaptonemal complex proteins. Furthermore, we will explore the role of candidate signaling molecules identified in a preliminary RNAi screen. These complementary approaches will provide significant insights into a surveillance system that monitors crossover formation on each chromosome and allows for timely progression through meiosis.

Public Health Relevance

Errors during meiosis, a specialized cell division program that gives rise to egg and sperm, account for a high proportion of miscarriages and birth defects. The proposed research investigates a control mechanism that helps ensure that meiosis occurs correctly. Information gained from these studies will lay the foundation for treatment of human reproductive disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Hamlet, Michelle R
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Magee-Women's Research Institute and Foundation
United States
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Macaisne, Nicolas; Kessler, Zebulin; Yanowitz, Judith L (2018) Meiotic Double-Strand Break Proteins Influence Repair Pathway Utilization. Genetics 210:843-856
Ahuja, Jasvinder S; Sandhu, Rima; Mainpal, Rana et al. (2017) Control of meiotic pairing and recombination by chromosomally tethered 26S proteasome. Science 355:408-411
Hillers, Kenneth J; Jantsch, Verena; Martinez-Perez, Enrique et al. (2017) Meiosis. WormBook 2017:1-43
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Amrit, Francis Raj Gandhi; Steenkiste, Elizabeth Marie; Ratnappan, Ramesh et al. (2016) Correction: DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans. PLoS Genet 12:e1006381
Mainpal, Rana; Yanowitz, Judith L (2016) A twist of fate: How a meiotic protein is providing new perspectives on germ cell development. Worm 5:e1175259
Mateo, Abigail-Rachele F; Kessler, Zebulin; Jolliffe, Anita Kristine et al. (2016) The p53-like Protein CEP-1 Is Required for Meiotic Fidelity in C. elegans. Curr Biol 26:1148-58
McClendon, T Brooke; Mainpal, Rana; Amrit, Francis R G et al. (2016) X Chromosome Crossover Formation and Genome Stability in Caenorhabditis elegans Are Independently Regulated by xnd-1. G3 (Bethesda) 6:3913-3925
McClendon, T Brooke; Sullivan, Meghan R; Bernstein, Kara A et al. (2016) Promotion of Homologous Recombination by SWS-1 in Complex with RAD-51 Paralogs in Caenorhabditis elegans. Genetics 203:133-45
Amrit, Francis Raj Gandhi; Steenkiste, Elizabeth Marie; Ratnappan, Ramesh et al. (2016) DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans. PLoS Genet 12:e1005788

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