Meiosis

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

We are trying to understand how the genetic information contained in the chromosomes is accurately transmitted from parents to offspring. This requires that gametes (sperm and eggs) carry the correct number of chromosomes before they fuse to form an embryo. Gametes are a special type of cells in that they only carry half the number of chromosomes that are present in other cells, otherwise the chromosome number would be duplicated in each generation. This chromosome halving is achieved by a special cell division program called meiosis. When this process fails gametes receive the wrong number of chromosomes, which leads to miscarriages and birth defects such as Down syndrome. We know the basic series of events that chromosomes undergo during meiosis, however, we understand very little about how these events are controlled. Our research is focused in first identifying the proteins that promote correct chromosome segregation during meiosis, and then investigating the precise role of each protein. In our studies we use a nematode worm, C. elegans, in which we can study how chromosomes behave in strains that lack different meiotic proteins. In the long term, we hope that our research will help us understand how meiosis works in humans.

Technical Summary

The ultimate goal of our group is to understand the molecular mechanisms that ensure the faithful segregation of chromosomes during meiosis, the specialized cell division program that forms haploid gametes from diploid germ cells. Correct chromosome partitioning during meiosis is achieved through a series of complex changes at the level of DNA molecules, chromosome structure and nuclear organization. These include: pairing of homologous chromosomes, the assembly of a proteinaceous scaffold (the synaptonemal complex) between the homologues, and the formation of crossover recombination events between DNA molecules of paired homologues. Crucially, inter-homologue crossovers provide the basis of a temporary physical link that holds homologues together until they segregate from each other on the first meiotic spindle. A failure to form crossovers results in the creation of aneuploid gametes, one of the leading causes of miscarriages and birth defects in humans. Our main focus is to elucidate the mechanisms that control the formation and distribution of inter-homologue crossovers during meiosis. We are using C. elegans as an experimental organism and a combination of different experimental approaches including: genetics, biochemistry, molecular biology and three-dimensional microscopy. Our research program is divided into two main areas: first, we are performing genetic screens to isolate mutants that display a reduced number of crossovers and second, we are investigating the molecular mechanisms by which HTP-1, a component of meiotic chromosome axes, promotes proper homologue pairing and crossover formation. We are also studying the interplay between crossovers and meiotic chromosome structure. We have shown that crossovers trigger a remodelling of chromosome axis composition that is required for proper homologue segregation, and that HTP-1 is a key player in this remodelling process. We are trying to identify proteins that collaborate with HTP-1 in this process. Studies are also directed at understanding the mechanisms that control the distribution of crossovers across the genome.

Publications

10 25 50
 
Description ??Imaging cellular structure and function beyond the diffraction limit
Amount £200,000 (GBP)
Funding ID MR/K015834/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2013 
End 01/2017
 
Description Core funding from MRC to LMS Meiosis group
Amount £1,800,000 (GBP)
Funding ID MC-A652-5PY60 
Organisation Medical Research Council (MRC) 
Department MRC Clinical Sciences Centre (CSC)
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2020
 
Description EMBO long term Fellowship
Amount £60,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Charity/Non Profit
Country Germany
Start 07/2015 
End 06/2017
 
Description Imperial College Lectureship
Amount £170,000 (GBP)
Organisation Imperial College London 
Department Imperial College Trust
Sector Charity/Non Profit
Country United Kingdom
Start 12/2011 
End 11/2014
 
Description In 2009 I moved to the Clinical Sciences Centre at Imperial College, and as part of this move I received a core-funded grant from the MRC to investigate the molecular mechanisms that promote correct chromosome segregation during meiosis. This is a five ye
Amount £900,000 (GBP)
Funding ID MC-A652-5PY60 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2009 
End 09/2014
 
Title Antibodies against meiotic proteins 
Description These antibodies can be used in Cell Biology and Biochemical experiments 
Type Of Material Antibody 
Provided To Others? No  
Impact These antibodies are important resource for our research program, and we will also distribute them to other research groups. 
 
Title C elegans mutants with defects in meiotic chromosome segregation 
Description Mutants generated in our laboratory to study the mechanisms that ensure correct chromosome segregation into the gametes. 
Type Of Material Cell line 
Year Produced 2010 
Provided To Others? Yes  
Impact The collection of meiotic mutants that we are generating are allowing us to identify novel genes required for chromosome segregation during meiosis. 
 
Title C elegans transgenic strains 
Description We have produced C elegans transgenic strains carrying different fluorescently tagged proteins that will allow the study of meiotic chromosome dynamics in vivo, as well as the measurement of different metabolites. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact This research material has been provided to other groups to improve the development of in vivo imaging techniques to measure metabolite levels at the whole organism level. 
 
Title Proteomics with C elegans germ cells 
Description We have developed methods to perform proteomic experiments using gem cells from C elegans. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact We have started two collaborations with groups in the USA and Canada, who are interested in our methodology. Other groups have asked for the protocols developed in our lab. The methodology will be reported in publication that is currently under preparation. 
 
Description APP1 Simon Boulton 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Collaboration with the CRUK to investigate the role of APP1 in human cells.
Collaborator Contribution Investigate how knock down of APP1 affects genome stability in human cells.
Impact 0
Start Year 2008
 
Description Analysis of meiosis in recombination mutants 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Experiments to determine pairing and recombination in different meiotic mutants. Writing manuscripts.
Collaborator Contribution Publications
Impact Publications: 20598602 and 20122407
Start Year 2008
 
Description Anne Villeneuve HAL2 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Immunoprecipitation experiments to identify binding partners of the HAL-2 protein in the nematode C elegans.
Collaborator Contribution Characterisation of meiotic defects in C elegans nematodes lacking the HAL-2-interacting protein HAL-3.
Impact Publication: doi: 10.1534/genetics.119.302479.
Start Year 2016
 
Description Anne Villeneuve HAL2 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Immunoprecipitation experiments to identify binding partners of the HAL-2 protein in the nematode C elegans.
Collaborator Contribution Characterisation of meiotic defects in C elegans nematodes lacking the HAL-2-interacting protein HAL-3.
Impact Publication: doi: 10.1534/genetics.119.302479.
Start Year 2016
 
Description Apoptosis and procrossover factors 
Organisation National Research Council
Department Institute of Genetics and Biophysics (IGB)
Country Italy 
Sector Public 
PI Contribution Investigating how different crossover-promoting factors participate in the selective culling of damaged germ cells.
Collaborator Contribution Performed the first experiments to demonstrate the involvement of crossover-promoting proteins in the apoptotic response.
Impact Publication: PMID: 23832114
Start Year 2010
 
Description In vivo analysis of metabolic reportes in C elegans 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution We are producing transgenic C elegans strains carrying different fluorescent reporters that allow the measurement of specific metabolites in living worms.
Collaborator Contribution This collaboration is allowing us to gain expertise in a new field or research for our laboratory, and is expected to bring new imaging techniques that will play an important role in future projects.
Impact This collaboration is allowing us to gain expertise in a new field or research for our laboratory, and is expected to bring new imaging techniques that will play an important role in future projects.
Start Year 2011
 
Description Interplay between cohesin and DNA damage 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution This collaboration has resulted in an open exchange of ideas that is benefiting both laboratories.
Collaborator Contribution This collaboration has resulted in an open exchange of ideas that is benefiting the design of experiments in our laboratory.
Impact This collaboration has resulted in an open exchange of ideas that is benefiting the design of experiments in our laboratory. Publication: Aragon L, Martinez-Perez E, Merkenschlager M. (2013). Condensin, cohesin and the control of chromatin states. Curr Opin Genet Dev 23(2):204-11.
Start Year 2011
 
Description Meiotic roles of the APP-1 amino peptidase 
Organisation University of Leeds
Department School of Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have uncovered an important for the APP-1 aminopeptidase during meiotic recombination in C. elegans. We have used a combination of cytology, genetics, and biochemistry to demonstrate that DNA damage accumulates in the absence of APP-1, and that this damage is repaired by error-prone mechanisms.
Collaborator Contribution This collaboration has granted us access to genetic reagents developed by the Isaac lab, and we are also benefiting from the expertise of Prof Isaac in the biology of amino peptidases.
Impact This collaboration has granted us access to genetic reagents developed by the Isaac lab, and we are also benefiting from the expertise of Prof Isaac in the biology of amino peptidases.
Start Year 2007
 
Description Monica LAB-1 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Investigating mechanisms that regulate recruitment of Aurora B kinase to chromosomes during meiosis in C elegans
Collaborator Contribution Creating C elegans strains carrying specific mutations in the LAB-1 protein to investigate the role of this protein in regulating Aurora B recruitment during C elegans meiosis.
Impact Publication: PMID: 29483514
Start Year 2015
 
Description Peter Carlton, Kyoto University (Japan) 
Organisation University of Kyoto
Country Japan 
Sector Academic/University 
PI Contribution Provided C. elegans strains generated in our group for analysis of protein localization on chromosomes.
Collaborator Contribution Genetic and cytological analysis of C elegans worms carrying mutations on the HIM-3 protein.
Impact Publication: doi: 10.1371/journal.pgen.1008968
Start Year 2019
 
Description Phospho proteomics JoAnne 
Organisation University of California, Davis
Department UC Davis College of Biological Sciences
Country United States 
Sector Academic/University 
PI Contribution Sharing phophorylation data generated in our group with the group at UC Davis
Collaborator Contribution The group at UC Davis is performing in vivo experiments to determine the functional relevance of phosphorylation identified by our group.
Impact This collaboration is mentioned as part of a NIH grant application by the group at UC Davis
Start Year 2016
 
Description Phospho proteomics Verena 
Organisation University of Vienna
Country Austria 
Sector Academic/University 
PI Contribution Sharing phosphorylation data of C elegans proteins generated by our group
Collaborator Contribution In vivo investigation of phosphorylation sites identified in our group
Impact Publication: doi: 10.1016/j.devcel.2018.03.018.
Start Year 2014
 
Description Phospho proteomics during meiosis 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution We are performing phospho proteomics experiments to identify the targets of the protein kinase that plays important roles duirng early meiosis.
Collaborator Contribution Create the transgenic strains required for these experiments.
Impact No outcomes to report yet, as this collaboration has just started.
Start Year 2013
 
Description Recombination in wheat 
Organisation John Innes Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution The main goal of this project is to understand the control of meiotic recombination in wheat. Understanding the molecular mechanisms that control this process could have an important impact on wheat breeding programs.
Collaborator Contribution This collaboration is resulting in an open exchange of information that is helping us to design some of our experiments.
Impact This collaboration is resulting in an open exchange of information that is helping us to design some of our experiments.
Start Year 2010
 
Description Role of N-terminal acetyl transferease during meiosis 
Organisation Harvard University
Department Department of Genetics
Country United States 
Sector Academic/University 
PI Contribution Isolation of C elegans carrying a mutation in the NatB homologue, and discovery of the meiotic role of this gene. Creation of transgenic strains carrying NatB transgenes.
Collaborator Contribution investigation of other components of this complex.In depth phenotypic analysis of the NatB mutant.
Impact Publication: PMID: 27881602
Start Year 2012
 
Description Role of RAD-51 paralogs in DNA repair 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated transgenic C elegans strains for in vivo experiments of RAD-51 paralogs function
Collaborator Contribution The Rueda (LMS) and Boulton (The Francis Crick Institute) groups have performed biochemical and single molecule experiments on the function of RAD-51 paralogs.
Impact Pubication: doi: 10.1016/j.molcel.2020.12.020. This is a multi-disciplinary collaboration, involving bio-physics and cell biology.
Start Year 2018
 
Description Role of RAD-51 paralogs in DNA repair 
Organisation Imperial College London
Department MRC London Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated transgenic C elegans strains for in vivo experiments of RAD-51 paralogs function
Collaborator Contribution The Rueda (LMS) and Boulton (The Francis Crick Institute) groups have performed biochemical and single molecule experiments on the function of RAD-51 paralogs.
Impact Pubication: doi: 10.1016/j.molcel.2020.12.020. This is a multi-disciplinary collaboration, involving bio-physics and cell biology.
Start Year 2018
 
Description Role of protein phosphatase 4 during meiosis 
Organisation University of Kyoto
Department Institute of Integrated Cell Material Sciences
Country Japan 
Sector Academic/University 
PI Contribution Isolation of mutants in the C elegans pph-4 gene, and description of meiotic phenotypes.
Collaborator Contribution Investigations of other alleles of pph-4, and detailed analysis of the role of this protein during meiosis.
Impact Publication: PMID: 25340746
Start Year 2012
 
Description Sarkies collaboration 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution Generation of transgenic C elegans strains to investigate the contribution of chromatin environment to piRNA biogenesis.
Collaborator Contribution Used sequencing and bioinformatic approaches to identify chromatin environment and motifs associated with piRNAs in different nematode species.
Impact Publication: PMID 30713076
Start Year 2018
 
Description Structural studies of meiotic proteins 
Organisation Imperial College London
Department Department of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have proposed a PhD project that required collaboration with an structural biology lab. We will perform in vivo experiments to test the predictions made from the structural studies
Collaborator Contribution Expertise in structural biology and access to the required equipment.
Impact Intercampus Collaborative Studentship from Imperial College awarded to fund the project
Start Year 2013
 
Description Super resolution microscopy 
Organisation Imperial College London
Department Department of Physics
Country United Kingdom 
Sector Academic/University 
PI Contribution Design PhD proposal to investigate meiotic chromosome structure using super resolution microscopy.
Collaborator Contribution Develop super resolution microscope systems that can be used to investigate meiotic chromosome structure.
Impact PhD studentship awarded Publication: doi: 10.1002/jbio.201800087
Start Year 2013
 
Description Lab demonstration for students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Secondary school children participated in a workshop in which members of my group show them how to use microscopes
Year(s) Of Engagement Activity 2017
 
Description Lab visited by school 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact During science week, several lab members (including myself) participated in outreach activities for KS2 children and A level students. This included organizing and running microscope workshops, presenting a seminar about our research, and a visit to our lab by A level students.
Year(s) Of Engagement Activity 2015,2016
 
Description Next steps workshop, Waldegrave 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Discussing a career in science with year 10-12 students who are thinking about future career choices
Year(s) Of Engagement Activity 2017
 
Description School visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Presentation during Science assembly to 180 children, plus microscopy workshops with 6 different classes of 30 children.
Year(s) Of Engagement Activity 2017
 
Description School visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talked about science during a KS1 assembly (180 year 1 and year 2 children) and then organized a microscope workshop attended by all children.
Year(s) Of Engagement Activity 2015,2016
 
Description School visit Strand on the Green 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Visit to Strand on the Green Infant school during science week. Talk and demonstration during assembly attended by 9 classes (around 180 children), followed by microscopy workshop for all classes during several hours.
Year(s) Of Engagement Activity 2018
 
Description School visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 90 pupils from a primary school were shown different samples on a microscope, and they learned about how experiments are carried out.

We have now expanded these visits to more classes, as the response from the students was very positive and the teachers asked for the continuation of these visits.
Year(s) Of Engagement Activity 2011,2012,2013,2014
 
Description Waldegrave school visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Visit to a secondary school in London to describe work in our laboratory
Year(s) Of Engagement Activity 2017
 
Description Year 10 work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Hosting two year 10 students during a week for work experience.
Year(s) Of Engagement Activity 2018
 
Description year 10 experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Two year 10 students spent a week in our group to gain work experience.
Year(s) Of Engagement Activity 2017