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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM104007-02
Application #
8608559
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Hamlet, Michelle R
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$268,718
Indirect Cost
$32,692
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
119132785
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zevian, Shannin C; Yanowitz, Judith L (2014) Methodological considerations for heat shock of the nematode Caenorhabditis elegans. Methods 68:450-7