Molecular Basis of Mesoderm Formation

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

My research investigates the mechanisms of early embryonic development. This is an important topic for two reasons. First, one in six couples have difficulty conceiving a child, a quarter of human conceptions are lost in the first five months, and 2% of children are born with a major genetic defect. Understanding developmental mechanisms can help alleviate these problems. Second, if we understand the mechanisms of normal embryonic development, we can use this information to help direct stem cell differentiation. Much of our work uses the accessible embryos of the frog and the zebrafish, but we also study the mouse as well as mouse and human embryonic stem cells. One of our objectives is to ask to what extent developmental mechanisms are conserved between species.

Technical Summary

My research group investigates mesoderm formation in the early vertebrate embryo. The mesoderm is the layer of cells that lies between the ectoderm and the endoderm and eventually goes on to form tissues such as muscle, heart, kidney, blood and bone. An understanding of how this germ layer is formed is key to all attempts to understand cell and tissue differentiation. We are interested in the signals that pass between cells to induce the mesoderm, in the ways in which those signals traverse a field of responding cells and come to be distributed in a graded fashion, in the ways in which cells interpret different concentrations of morphogens to activate the expression of different target genes, and the ways in which those genes, once activated, direct the formation of different cell types. Much of our work uses embryos of the South African claw-toed frogs Xenopus laevis and Xenopus tropicalis, but in an effort to ensure that our results are of general applicability, we also study the zebrafish Danio rerio and the mouse. In addition, one particular focus of our research is to ask to what extent mesoderm formation in embryos resembles the process as it occurs in human and mouse embryonic stem cells, in the hope that our work might assist efforts to direct stem cell differentiation and ultimately the formation of functioning tissues and organs in vitro.|Much of our work focuses on Brachyury and other members of the T box family of transcription factors. These proteins are both necessary and sufficient for proper mesoderm formation, and an understanding of their regulation and function will be key to understanding how the mesoderm is specified and patterned. We are using transgenic animals to understand the transcriptional regulation of the T box genes, and chromatin immunoprecipitation and high-throughput sequencing to identify target genes. Our objective is to understand the genetic regulatory network that is initiated and maintained by the T box genes, including the direct interactions between transcription factor and target genes as well as the signal transduction pathways that mediate interactions between cells.

Publications

10 25 50

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Nurse P (2013) Building better institutions. in Science (New York, N.Y.)

 
Description Board memebr, HDR-UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL https://www.mrc.ac.uk/news/browse/initial-board-appointments-for-health-data-research-uk/
 
Description British Library Advisory Board
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Indian Institute of Science Education and Research
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description Institute for Toxicology and Genetics, Karlsruhe
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
 
Description Membership of Council of the Academy of Medical Sciences
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://acmedsci.ac.uk/about/governance/council-members
 
Description SAB, Biosciences & Bioengineering Group, Indian Institute of Technology,
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description Wellcome Trust Investigator Award panel
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
 
Description Wellcome Trust/Royal Society Henry Dale panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description EU-Networks for Initial Training (ITN)
Amount £367,221 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 06/2009 
End 07/2012
 
Description European Training Network for Developmental and Computational Biology
Amount € 285,057 (EUR)
Funding ID PITN-GA-2013-607142 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2013 
End 08/2017
 
Description Fondation Leducq
Amount £283,761 (GBP)
Organisation The Leducq Foundation 
Sector Charity/Non Profit
Country France
Start 10/2010 
End 09/2015
 
Description Wellcome Trust
Amount £296,336 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2015
 
Description Ladybird gene function 
Organisation University of Vienna
Country Austria 
Sector Academic/University 
PI Contribution Use of Xenopus embryos to understand gene function.
Collaborator Contribution Use of Nematostella embryos to understand gene function.
Impact Papers in preparation.
Start Year 2009
 
Description Regulation of the MBT 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in early Xenopus tropicalis development.
Collaborator Contribution Expertise in cell cycle regulation
Impact Collart C, Allen GE, Bradshaw CR, Smith JC, Zegerman P. (2013). Titration of four replication factors is essential for the Xenopus laevis midblastula transition.Science 341, 893-6. doi: 10.1126/science.1241530.
Start Year 2015
 
Description T-box gene function in human ES cells 
Organisation Medical Research Council (MRC)
Department MRC Centre For Stem Cell Biology
Country United Kingdom 
Sector Public 
PI Contribution Expertise in the T-box gene family
Collaborator Contribution Expertise in human ES cell culture
Impact PMID: 21816365
Start Year 2008
 
Description Xenopus MBT transcriptome 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Embryological experiments and sequencing.
Collaborator Contribution Data analysis
Impact Collart, C., Owens, N.D.L., Bhaw-Rosun, L., Cooper, B., De Domenico, E., Sesay, A.K., Smith, J.N., Patrushev, I., Smith, J.C. and Gilchrist, M.J. (2014). High-resolution analysis of gene activity during the Xenopus mid-blastula transition. Development 141, 1927-1939.
Start Year 2009
 
Description Zebrafish MBT 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Intellectual contributions, sequencing, and writing of the paper.
Collaborator Contribution Breeding fish, sequencing, data analysis.
Impact Harvey, S.A., Sealy, I., Kettleborough, R., Feynes, F., White, R., Stemple, D. and Smith, J.C. (2013). Identification of the zebrafish maternal and paternal transcriptomes. Development 140, 2703-2710.
Start Year 2010
 
Description AMS Academic Careers Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Talk influenced content of report

Report was influenced by my comments
Year(s) Of Engagement Activity 2015
 
Description British Library Advisory Council 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Meeting raised interesting questions about the future of the British Library.

Frequency of advisory council meetings increased; interesting discussions of 'knowledge quarter'.
Year(s) Of Engagement Activity 2014
 
Description Cambridge developmental biologists 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk sparked questions and discussion afterwards.

None
Year(s) Of Engagement Activity 2015
 
Description Crick Internal Update 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact 100 people attended a Crick update

Increased engagement with Crick project
Year(s) Of Engagement Activity 2012
 
Description Crick Workshop on Reverse Translation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 100 people attended Crick workshop

Increased awareness of Crick porject
Year(s) Of Engagement Activity 2012
 
Description Crick talk at King's 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk sparked questions and discussion afterwards

Increased interest in the Crick afterwards
Year(s) Of Engagement Activity 2015
 
Description Foreign sisters 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Supporters
Results and Impact Financial contributions to CRUK

Further interactions with CRUK
Year(s) Of Engagement Activity 2015
 
Description Gurdon Institute Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 200 attended symposium

Increased awareness of Crick and NIMR
Year(s) Of Engagement Activity 2012
 
Description Health Tech 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk sparked questions and discussion afterwards.

Talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description Latymer pupil 
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 Sixth former worked for 6 weeks in the lab.

Great enthusiasm from pupil and school.
Year(s) Of Engagement Activity 2011
 
Description Lichfield Science and Engineering Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk about embryology and the Francis Crick Institute
Year(s) Of Engagement Activity 2017
URL http://www.lses.org.uk/author/lses-admin/
 
Description Liverpool lab design 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact About 200 experts in lab design attended an dherd how the Crick will function.

Asked to contribute to other meetings on lab design.
Year(s) Of Engagement Activity 2013
 
Description Mill Hill Historical Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and comment.

Interest of participants in coming to NIMR to learn more.
Year(s) Of Engagement Activity 2014
 
Description Mill Hill School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk sparked questions and interest and elicited questions about careers.

Interest from a student wanting to do a PhD
Year(s) Of Engagement Activity 2015
URL http://www.millhill.org.uk/news/lectures.html
 
Description NIMR Centenary Meeting 
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 Professional Practitioners
Results and Impact Event brought together alumni of NIMR.

Many tweets and interest from NIMR alumni.
Year(s) Of Engagement Activity 2014
 
Description Nature Careers Expo 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact My talk sparked many questions, tweets and blogs

Blogs and tweets
Year(s) Of Engagement Activity 2014
 
Description One science: life at the interface 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Increased awareness of the strategy of the Francis Crick Institute
Year(s) Of Engagement Activity 2015
 
Description RVC Council meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Increased awareness of the Francis Crick Institute
Year(s) Of Engagement Activity 2015
 
Description Regents College Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 50 people attended talk about Crick Institute

Increased awareness of Crick
Year(s) Of Engagement Activity 2012
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact About 120 pupils. They seemed to enjoy it.

They came back the following year.
Year(s) Of Engagement Activity 2010
 
Description Science Museum Late 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk was tweeted about and was mentioned as one of the highlights of the event.

None
Year(s) Of Engagement Activity 2014
URL http://www.crick.ac.uk/news/news-archive/2014/02/27/record-breaking-attendance-at-crick-event/
 
Description Talk at Camden School for Girls 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact About 30 pupils came to a talk about embryology and the Francis Crick Institute
Year(s) Of Engagement Activity 2017
 
Description U3A 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 120 older people attended lecture; some discussion afterwards

They came back the following year.
Year(s) Of Engagement Activity 2009,2010
 
Description UCL Research Awayday 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussion about Francis Crick Institute

Increased awareness of Francis Crick Institute
Year(s) Of Engagement Activity 2014
 
Description Warwick seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015