Chromosome segregation in mammalian meiosis

Lead Research Organisation: University of Oxford
Department Name: Biochemistry

Abstract

We are trying to identify mechanisms that ensure each egg receives a single copy of every chromosome. The inheritance of too many or too few chromosomes can result in spontaneous miscarriages or severe birth defects as in Down’s Syndrome or trisomy of chromosome 21.

We know that cells in the body regulate the equal distribution of chromosomes by entrapping sister chromosomes within protein rings. These rings are only destroyed when cells are ready to divide.

In women, the rings must hold together sister chromosomes in eggs from birth until fertilization, which can be separated by decades. We are investigating how these rings are stably maintained. Loss of rings over time could be responsible for maternal age-related infertility.

We are using animal models to study chromosome segregation in eggs with the aim to understand the equivalent processes in humans. We are studying eggs lacking specific proteins that are known to be important for chromosome segregation in other organisms. We are taking movies of mutant eggs carrying fluorescently labelled chromosomes to identify which aspects of chromosome segregation are defective due to loss of a particular protein. We also hope to identify new regulators of the egg divisions by studying infertile mutants.

Technical Summary

Our objective is to gain a greater understanding of the molecular mechanisms regulating chromosome segregation during mammalian meiosis. Meiosis consists of two rounds of chromosome segregation, in which bivalent chromosomes are first converted to univalents and then univalents to single chromatids. We are taking two approaches to study these mechanisms in the mouse, with the ultimate goal of understanding better the equivalent processes in women. We have adopted a genetic approach in which oocytes with specific gene deletions are observed in real time using time lapse microscopy as they undergo the first and second meiotic divisions. Our first approach recognizes that many if not most of the proteins that drive meiosis are also involved in mitosis and are therefore essential for development and oogenesis. To create oocytes that lack these proteins, we have developed a method that removes the proteins specifically from oocytes that have undergone recombination but before they undergo chromosome segregation. Briefly, we use the Zp3-cre transgene to delete both copies of floxed alleles of genes known to be important for mitosis during the growing stage of oocytes. Since the generation of conditional alleles is relatively labour-intensive, this approach is only applied to a few specific genes about which we have posed very specific questions as to their function during meiosis. The approach is hypothesis-driven and its limitation is that new unknown players will be not be discovered. We therefore plan to complement this approach by one that could identify genes required for the meiotic divisions for which there is no prior knowledge of their function. Our second approach relies on identifying sterile or sub-fertile mutants in a large-scale screen of novel knockout mice carried out by the Mouse Genetics Programme at the Wellcome Trust Sanger Institute. We test whether these mutants still produce oocytes and, if so, analyse them using live-cell imaging technology and chromosome spreads. Mutants displaying defects in chromosome segregation provide candidates for proteins that might deteriorate in aging oocytes and could explain the maternal age effect. To date, we lack an understanding of the phenomenon that the risk of producing aneuploid oocytes increases by more than two logs in human females between the ages of 24 and 45. Our research aimed at identifying novel regulators of meiotic chromosome segregation will eventually provide insight into chromosome non-disjunction in older women.
 
Title Meetings Of Minds Documentary Trailer 
Description The Meeting of Minds is a documentary about the MitoSys Project! The film explores the subject of mitosis through conversations between scientists and artists, bringing new, creative perspectives to the topic. Kim Nasmyth is one of the 4 scientists featured in the film, alongside Jan-Michael Peters, Tony Hyman, and Melina Schuh. 
Type Of Art Film/Video/Animation 
Year Produced 2014 
Impact For many people not involved in the world of science, scientific concepts can be hard to grasp. The documentary, Meetings of Minds, made within the context of the exhibition LENS ON LIFE, invites 4 artist/ scientist teams to explore, and make accessible, concepts and processes belonging to a world invisible to the senses and usually confined to the guarded enclosures of the scientific laboratory. 
URL http://hymanlab.mpi-cbg.de/hyman_lab/meetings-of-minds-a-documentary-about-the-mitosys-project/
 
Description Maternal age effect
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description ERC ADVANCED GRANT
Amount € 2,000,000 (EUR)
Funding ID Proposal No 294401 
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 05/2012 
End 05/2017
 
Title On-line resource 
Description Database of Nasmyth lab plasmids and yeast strains available to the scientific community 
Type Of Material Biological samples 
Provided To Others? Yes  
Impact Plasmids and yeast strains are available for free to the scientific community. Saves time for other researchers, no need for cloning the same thing again. 
URL https://www.bioch.ox.ac.uk/research/nasmyth
 
Title Nasmyth group databases containing all plasmids and strains created in the Nasmyth lab since 1970 
Description The yeast strain repository contains over 22,000 strains stored as glycerol stocks in an annotated -80°C freezer storage system. The plasmid repository contains over 6000 plasmids in numerous different vectors, including cloned cDNA and genomic fragments of cohesin and cohesin related genes from Saccharomyces cerevisiae and number of other different species. The clones include plasmid vectors useful for routine and cutting-edge techniques. Information about vectors and plasmid clones, including maps and sequence data. We share plasmids and yeast strains freely with the scientific community. Samples can be requested from our webpage (http://www.bioch.ox.ac.uk/aspsite/research/nasmythform.html) 
Type Of Material Database/Collection of data 
Provided To Others? Yes  
Impact The databases serves as a central data repository and enables researchers to search the collections using strain names, common gene names and identifiers, keywords, vector features, author names etc. If the strain or plasmid is in the collection we will send it to the scientists requesting. This saves time, money and energy. 
URL https://www.bioch.ox.ac.uk/research/nasmyth
 
Description Role of Sgol2 in mammalian meiosis 
Organisation Spanish National Research Council (CSIC)
Department Institute of Molecular and Cellular Biology of Cancer (IBMCC)
Country Spain 
Sector Public 
PI Contribution We characterised multiple roles of Sgol2 in mammalian meiosis
Collaborator Contribution Alberto Pendas' group generated Sgol2 knockout mice
Impact We have recently published our results in eLife (http://elife.elifesciences.org/content/2/e01133)
Start Year 2010
 
Description Role of Shugoshin-like protein 2A in mammalian meiosis 
Organisation University of Bayreuth
Department Department of Genetics
Country Germany 
Sector Academic/University 
PI Contribution We found the role of Sgol2 and Mad2 in mammalian meiosis. We have recently published our results in eLife.
Collaborator Contribution Olaf Stemmann's group at the University of Bayreuth performed far-western blots to confirm in-vitro interaction between Sgol2 and Mad2.
Impact We have recently published our results in eLife: http://elife.elifesciences.org/content/2/e01133
Start Year 2011
 
Description Role of key proteins in holding together chromosomes 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution New research by scientists in the department of Biochemistry, University of Oxford and at the Sanger Institute has provided definitive molecular evidence for the role of key proteins in holding together the chromosomes of mammalian eggs until the egg is ready for fertilisation. Deterioration of these proteins could explain why birth defects increase and fertility decreases as women become older, a phenomenon known as the maternal age effect.
Collaborator Contribution Mouse lines provision
Impact PMID:20971813
Start Year 2006
 
Title Why chromosomes may start to show their age 
Description We suggest that the inability of oocytes to regenerate cohesion may contribute to age related meiosis I errors. Deterioration of these proteins could explain why birth defects increase and fertility decreases as women become older, a phenomenon known as the maternal age effect. The principal source of funding are academic research grants. 
Type Preventative Intervention - Physical/Biological risk modification
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact The research throws up the tantalising possibility that cohesin is stable on the chromosomes for the entire duration of oocyte existence. For humans, this may be decades. In contrast, most proteins stay around the cell for a matter of hours. 'If this is the case, then the idea is consistent with cohesin decay over time being responsible for the maternal age effect. 
 
Description Departmental website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Our Departmental website features news highlights of the latest scientific findings from within the Department, written primarily for a general audience.

It enables students and researchers to find out about the type of research we do and apply via contact emails provided.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2020
URL http://www.bioch.ox.ac.uk
 
Description Meetings-of-minds documentary about the mitosys project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The film centres on the collaboration between four pairs of artists and scientists, and combines four short films that represent the artist's responses to the scientist's work on cell division. The film is directed by Natasha Serlin and will be screened from 2014 onwards at schools, universities and other institutes of further education, science festivals, art galleries and film / documentary festivals.

For many people not involved in the world of science, scientific concepts can be hard to grasp. The documentary, Meetings of Minds, made within the context of the exhibition LENS ON LIFE, invites 4 artist/ scientist teams to explore, and make accessible, concepts and processes belonging to a world invisible to the senses and usually confined to the guarded enclosures of the scientific laboratory.
Year(s) Of Engagement Activity 2013,2014
URL http://hymanlab.mpi-cbg.de/hyman_lab/meetings-of-minds-a-documentary-about-the-mitosys-project/
 
Description Work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact Each year we share our work and experience with up to four seventeen year olds interested to pursue a career in science or medicine.

A number of them have stayed in touch and are now university students.
Year(s) Of Engagement Activity 2011,2012,2013,2017,2018,2019
URL http://www.bioch.ox.ac.uk/aspsite/index.asp?pageid=591