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.
People |
ORCID iD |
| James Cuthbert Smith (Principal Investigator) |
Publications
Bernardo AS
(2011)
BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages.
in Cell stem cell
Bernardo AS
(2018)
Mammalian embryo comparison identifies novel pluripotency genes associated with the naïve or primed state.
in Biology open
Boname JM
(2014)
Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins.
in The Journal of cell biology
Bozatzi P
(2018)
PAWS1 controls Wnt signalling through association with casein kinase 1a.
in EMBO reports
Callery EM
(2012)
Eps15R is required for bone morphogenetic protein signalling and differentially compartmentalizes with Smad proteins.
in Open biology
Callery EM
(2010)
A divergent Tbx6-related gene and Tbx6 are both required for neural crest and intermediate mesoderm development in Xenopus.
in Developmental biology
Cannon JE
(2010)
Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists.
in British journal of pharmacology
Cannon JE
(2013)
Global analysis of the haematopoietic and endothelial transcriptome during zebrafish development.
in Mechanisms of development
Christov CP
(2018)
A NuRD Complex from Xenopus laevis Eggs Is Essential for DNA Replication during Early Embryogenesis.
in Cell reports
Collart C
(2013)
Titration of four replication factors is essential for the Xenopus laevis midblastula transition.
in Science (New York, N.Y.)
Collart C
(2014)
High-resolution analysis of gene activity during the Xenopus mid-blastula transition
in Development
Collart C
(2017)
Chk1 Inhibition of the Replication Factor Drf1 Guarantees Cell-Cycle Elongation at the Xenopus laevis Mid-blastula Transition.
in Developmental cell
Collart C
(2011)
The midblastula transition defines the onset of Y RNA-dependent DNA replication in Xenopus laevis.
in Molecular and cellular biology
Cummins TD
(2018)
PAWS1 controls cytoskeletal dynamics and cell migration through association with the SH3 adaptor CD2AP.
in Journal of cell science
Dingwell KS
(2018)
Dissecting and Culturing Animal Cap Explants.
in Cold Spring Harbor protocols
Evans AL
(2012)
Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells.
in PloS one
Eve A
(2017)
Knockdown of Laminin gamma-3 (Lamc3) impairs motoneuron guidance in the zebrafish embryo
in Wellcome Open Research
Eve AM
(2017)
Comparison of Zebrafish tmem88a mutant and morpholino knockdown phenotypes.
in PloS one
Faial T
(2015)
Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells.
in Development (Cambridge, England)
Fulcher LJ
(2018)
The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms.
in Science signaling
Gentsch GE
(2013)
In vivo T-box transcription factor profiling reveals joint regulation of embryonic neuromesodermal bipotency.
in Cell reports
Gentsch GE
(2017)
Efficient Preparation of High-Complexity ChIP-Seq Profiles from Early Xenopus Embryos.
in Methods in molecular biology (Clifton, N.J.)
Gentsch GE
(2014)
Investigating physical chromatin associations across the Xenopus genome by chromatin immunoprecipitation.
in Cold Spring Harbor protocols
Gentsch GE
(2018)
Innate Immune Response and Off-Target Mis-splicing Are Common Morpholino-Induced Side Effects in Xenopus.
in Developmental cell
Gentsch GE
(2015)
Genome-wide snapshot of chromatin regulators and states in Xenopus embryos by ChIP-Seq.
in Journal of visualized experiments : JoVE
| 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 |