Transcriptional Control of Vertebrate Limb Development
Lead Research Organisation:
MRC National Inst for Medical Research
Abstract
Abnormalities in normal heart formation are the most common birth defect, occurring in 1 in 120 live births. If uncorrected, these defects can have serious debilitating effects on quality of life and in severe cases lead to premature death. Other less life-threatening birth defects also dramatically decrease quality of life in affected individuals. Among these, limb defects are the most common. We are interested in studying the causes of two human syndromes that lead to serious abnormalities in normal heart and limb formation. Patients with Holt-Oram Syndrome (HOS) have severely malformed hearts and limbs and those with Ulnar-Mammary Syndrome (UMS) are afflicted with abnormal limb and mammary gland development.|In each syndrome the corruption of the genetic information in a single gene is sufficient to cause all of the associated abnormalities. Armed with this knowledge of the exact genetic cause of each syndrome we propose to investigate the underlying biology of these diseases. Using the mouse and chicken, we are generating syndrome models that provide a powerful method to understand how loss of normal gene function leads to the disruption of heart and limb formation. In both animal models, the development of the heart and limbs occurs in a similar manner to our own and each animal model has experimental advantages we can exploit. Understanding the genesis of these syndromes will provide information vital in order to devise more effective diagnostic and corrective treatments in human patients.
Technical Summary
Limb defects are the second most common congenital abnormality present in human live births and diseases affecting the musculoskeletal system are a significant clinical problem, particularly in the older population. The goal of our work is to understand how the limbs form normally during embryogenesis and the genesis of limb abnormalities and diseases that affect the musculoskeletal system in humans. ||Limbs are formed from specific regions of the flank of the embryo. At early stages of embryonic development, the forelimb and hindlimb buds are morphologically uniform and indistinguishable from one another. During subsequent steps of development however, dramatic changes take place. Each bud develops to form a network of interconnected limb elements e.g. bones, muscles, and tendons-with morphologies characteristic of either the forelimb or hindlimb. We are using vertebrate animal models to understand the mechanisms that control the initiation of limb bud formation and the subsequent construction of the individual limb elements during embryonic development. A longer-term aim is to apply these findings to develop to potential therapeutic approaches that could contribute to maintenance and possible regeneration of these structures in later life.||We use the developing limb as a model system using predominantly mouse and chick model organisms but also zebrafish and frog (and in future, as part of collaboration, we also plan to include Bat). In general our strategy is to interrogate gene function using a combination of coordinated gene misexpression and gene deletion experiments, often in more than one model system. In the mouse, we take advantage of gene conditional alleles and a repertoire of Cre deleter transgenics that we have developed ourselves or have collected. We often include transgene reporters to aid in phenotyping. In the chick, we are using genetic techniques to misexpress genes (either retroviral vectors or electroporation or direct application of recombinant proteins or substances) in combination with more classical embryological approaches. A new and important aspect of current and future work is to develop the use of in vitro techniques as an alternative, complementary approach to our in vivo models. Currently this involves the generation and characterisation of cell lines derived from transgenic reporter mouse lines we have produced and collected.|
Organisations
- MRC National Inst for Medical Research, United Kingdom (Lead Research Organisation)
- Guy's and St Thomas' NHS Foundation Trust, London (Collaboration)
- Guy's Hospital (Collaboration)
- Jeanne de Flandre Hospital (Collaboration)
- UCB Pharma, Belgium (Collaboration)
- Royal Free London NHS Foundation Trust, United Kingdom (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- Great Ormond Street Hospital Children's Charity (GOSHCC) (Collaboration)
- Medical Research Council (Collaboration)
People |
ORCID iD |
| Malcolm Logan (Principal Investigator) |
Publications
Abu-Daya A
(2011)
The secreted integrin ligand nephronectin is necessary for forelimb formation in Xenopus tropicalis.
in Developmental biology
Bickley SR
(2014)
Regulatory modulation of the T-box gene Tbx5 links development, evolution, and adaptation of the sternum.
in Proceedings of the National Academy of Sciences of the United States of America
Carkett MD
(2011)
1, 2, 3: counting the fingers on a chicken wing.
in Genome biology
Cenni C
(2021)
TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype.
in European journal of medical genetics
DeLaurier A
(2006)
Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb.
in Developmental biology
Delaurier A
(2008)
The Mouse Limb Anatomy Atlas: an interactive 3D tool for studying embryonic limb patterning.
in BMC developmental biology
Duboc V
(2009)
Building limb morphology through integration of signalling modules.
in Current opinion in genetics & development
Duboc V
(2021)
Tbx4 function during hindlimb development reveals a mechanism that explains the origins of proximal limb defects.
in Development (Cambridge, England)
Duboc V
(2011)
Regulation of limb bud initiation and limb-type morphology.
in Developmental dynamics : an official publication of the American Association of Anatomists
Duboc V
(2011)
Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control.
in Development (Cambridge, England)
Durland JL
(2008)
Visualizing the lateral somitic frontier in the Prx1Cre transgenic mouse.
in Journal of anatomy
Francis JC
(2005)
Notch1 signals through Jagged2 to regulate apoptosis in the apical ectodermal ridge of the developing limb bud.
in Developmental dynamics : an official publication of the American Association of Anatomists
Harvey S
(2006)
sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth
in Development
Hasson P
(2007)
Tbx5 is dispensable for forelimb outgrowth.
in Development (Cambridge, England)
Hasson P
(2010)
Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning.
in Developmental cell
Horton AC
(2008)
Conservation of linkage and evolution of developmental function within the Tbx2/3/4/5 subfamily of T-box genes: implications for the origin of vertebrate limbs.
in Development genes and evolution
Kmita M
(2005)
Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function.
in Nature
Manning L
(2006)
Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation.
in Developmental cell
Minguillon C
(2012)
Hox genes regulate the onset of Tbx5 expression in the forelimb.
in Development (Cambridge, England)
Minguillon C
(2009)
Tbx4/5 gene duplication and the origin of vertebrate paired appendages.
in Proceedings of the National Academy of Sciences of the United States of America
Minguillon C
(2005)
Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth.
in Developmental cell
Murphy GRF
(2017)
Correction of "Wrist" Deformity in Radial Dysplasia: A Systematic Review and Meta-Analysis.
in The Journal of bone and joint surgery. American volume
Nishimoto S
(2015)
RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation.
in Cell reports
Rallis C
(2005)
Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo.
in Development (Cambridge, England)
| Title | Collaboration with Tamsin van Essen |
| Description | Tamsin is a ceramicist-http://www.vanessendesign.com/- who is developing works based on interaction with the lab over the next 6 months |
| Type Of Art | Artwork |
| Year Produced | 2014 |
| Impact | work in progress |
| URL | http://www.vanessendesign.com/ |
| Title | Collaboration with artist Ju Gosling |
| Description | Abnormal Exhibition. Abnormal developed from Ju Gosling aka ju90's artist's residency at the National Institute of Medical Research (NIMR), which took place between 2006 - 2007. Funded by the Wellcome Trust, the residency explored ideas about normality, and asked whether there is a 'Scientific Model of Disability' that is distinct from the 'Medical Model of Disability'? The exhibition toured nationally from 2008-2012 |
| Type Of Art | Artistic/Creative Exhibition |
| Year Produced | 2010 |
| Impact | national touring exhibition, media coverage, permanent website for exhibition, book produced associated with exhibition |
| URL | http://www.scientificmodelofdisability.co.uk/ |
| Description | Contribution to WHO meeting on causes of Thalidomide Embryopathy |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
| URL | http://www.thalidomidetrust.org/thalidomide-embryopathy-world-health-organisation-report/ |
| Description | Member of Education Policy Advisory Panel (EPAG) for Gen Soc as part of Society of Biology |
| Geographic Reach | National |
| Policy Influence Type | Participation in a advisory committee |
| URL | https://www.societyofbiology.org/education |
| Description | Vice president corporate affairs, Genetics Society |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Description | Commonwealth Fellowship |
| Amount | £2,000 (GBP) |
| Organisation | Government of the UK |
| Department | Commonwealth Scholarship Commission |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2011 |
| End | 11/2012 |
| Description | EMBO Fellowship-2006 |
| Amount | £692 (GBP) |
| Organisation | European Molecular Biology Organisation |
| Sector | Charity/Non Profit |
| Country | Germany |
| Start | 04/2006 |
| End | 04/2008 |
| Description | EMBO Research Grant-2009 |
| Amount | £25,690 (GBP) |
| Organisation | European Molecular Biology Organisation |
| Sector | Charity/Non Profit |
| Country | Germany |
| Start | 03/2009 |
| End | 02/2011 |
| Description | EU-Intr-European Fellowship-IEF-(Limb-type ID) |
| Amount | £155,632 (GBP) |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 12/2010 |
| End | 11/2012 |
| Description | MRC Research Grant |
| Amount | £488,429 (GBP) |
| Funding ID | MR/S000038/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2019 |
| End | 06/2022 |
| Title | 3D Mouse Limb anatomy database |
| Description | An interactive 3D anatomy atlas of the embryonic mouse forelimb and hindlimb |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2008 |
| Provided To Others? | Yes |
| Impact | Improved Anatomy atlas that is more user-friendly and more stable across multiple platforms I get enquiries about the database The database is cited in publications |
| URL | https://www.emouseatlas.org/emap/ema/modelsummary/modelsummary.html |
| Title | Antibody |
| Description | Tbx5 antibody polyclonal |
| Type Of Material | Antibody |
| Provided To Others? | No |
| Impact | ongoing work functional antibody |
| Title | Mouse limb anatomy database |
| Description | The Interactive 3D Mouse Limb Anatomy Atlas is a free, downloadable resource of mouse limb anatomy at embryonic stage (E) 14.5 days gestation. Users build, rotate, magnify, and virtually dissect models of the limb using 3D datasets of real forelimbs and hindlimbs using the JAtlas Viewer program. Individual muscles, tendons, and bones are colour-coded and annotated, and users can manipulate 3D models and generate virtual sections through the specimen. |
| Type Of Material | Biological samples |
| Year Produced | 2008 |
| Provided To Others? | Yes |
| Impact | none |
| URL | http://www.nimr.mrc.ac.uk/3dlimb/ |
| Title | Pitx1 antibody |
| Description | Pitx1 antibody polyclonal |
| Type Of Material | Antibody |
| Provided To Others? | No |
| Impact | ongoing work |
| Title | Provider of transgenic mouse lines |
| Description | transgenic mouse lines eg Prx1Cre, Prx1CreERt2 |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2006 |
| Provided To Others? | Yes |
| Impact | numerous publications |
| Title | Prx1Cre and Prx1CreERt2 transgenic mouse lines |
| Description | Prx1Cre and Prx1CreERt2 transgenic mouse lines |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2010 |
| Provided To Others? | Yes |
| Impact | Continually requested research tools that are finding new uses for a broader range of studies including cancer studies Continually cited in published work |
| Title | Tbx4 Antibody |
| Description | Tbx5 antibody polyclonal |
| Type Of Material | Antibody |
| Provided To Others? | No |
| Impact | ongoing work |
| Title | provider of transgenic mouse lines |
| Description | transgenic mouse lines |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2010 |
| Provided To Others? | Yes |
| Impact | numerous publications |
| Description | Cited1/Tbx5 and Radial Dysplasia |
| Organisation | Jeanne de Flandre Hospital |
| Country | France |
| Sector | Hospitals |
| PI Contribution | Collaboration of causes of congenital limb defect |
| Collaborator Contribution | Collaboration of causes of congenital limb defect |
| Impact | Succesful MSc, now moved to PhD registration of student |
| Start Year | 2016 |
| Description | Collaboration with plastics and reconstructive surgeons |
| Organisation | Great Ormond Street Hospital Children's Charity (GOSHCC) |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | Hosting and collaborating with ploastic surgeons with specialities in reconstructive surgery of hand Mr Branivan Sivakumar Miss Gill Smith Dr George Murphy Dr Log Murugesan |
| Collaborator Contribution | Developing ongoing collaborative work to explore ways to improved surgical approaches and surgical outcomes in limb reconstructive surgery |
| Impact | Mres project completed and succesful production of preliminary data. plans for further work |
| Start Year | 2013 |
| Description | Collaboration with plastics and reconstructive surgeons |
| Organisation | Royal Free London NHS Foundation Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Hosting and collaborating with ploastic surgeons with specialities in reconstructive surgery of hand Mr Branivan Sivakumar Miss Gill Smith Dr George Murphy Dr Log Murugesan |
| Collaborator Contribution | Developing ongoing collaborative work to explore ways to improved surgical approaches and surgical outcomes in limb reconstructive surgery |
| Impact | Mres project completed and succesful production of preliminary data. plans for further work |
| Start Year | 2013 |
| Description | DECIPHER/DDD Radial Ray Defects^60 Holder-Espinasse |
| Organisation | Guy's Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | I have actively search for and established links with clinicians interested in limb defects. We have developed a strategy to identify patients/families for further study and the key goals for the short and medium term to best deliver impacst on improved patient care and to develop knowledge of the causes and treatments of limb defects |
| Collaborator Contribution | Provide the clinical lead in partnership and have direct access/contact with patients |
| Impact | only established in 2014 |
| Start Year | 2014 |
| Description | Quantifying the effects of treatments to reduce immunogenicity of tendon xeno/allografts |
| Organisation | Guy's and St Thomas' NHS Foundation Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Initiating a pilot study with a collaborator, Mr Adil Adjued, Consultant orthopaedic surgeon, GSST to quantify the effects of treatments to reduce immune response/rejevtion of tendon xeno or allografts for surgical replacement following tendon injury/failure. |
| Collaborator Contribution | Provide clinical link for study and samples for analysis |
| Impact | work ongoing. Follwoing results of pilot will (i) publish study in clinical journal (ii) explore possibiklity to extend collaboration and seek funding for further work |
| Start Year | 2016 |
| Description | Role of Tbx5 in limb soft tissue morphogenesis |
| Organisation | Medical Research Council (MRC) |
| Department | MRC National Institute for Medical Research (NIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Generation nof £D imaging data of limb development |
| Collaborator Contribution | Significantly refined our analysis |
| Impact | Peleg Hasson, April DeLaurier, Michael Bennett, Elena Grigorieva, L.A. Naiche, Virginia E. Papaioannou, Timothy J. Mohun, Malcolm P.O. Logan (2010) Tbx4 and Tbx5 acting in connective tissue are required for limb muscle and tendon patterning. Developmental Cell 18 (1) 148-156 PMID: 20152185 |
| Start Year | 2007 |
| Description | Role of nephronectin in forelimb development |
| Organisation | Medical Research Council (MRC) |
| Department | MRC National Institute for Medical Research (NIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Novel experimental approach adn observations |
| Collaborator Contribution | novel experimental approach and observations |
| Impact | Abu-Daya, A., Nishimoto, S., Fairclough, L., Mohun, TJ., Logan, MP., Zimmerman, LB. (2010) The secreted integrin ligand nephronectin is necessary for forelimb formation in Xenopus tropicalis Dev Biol Oct 23 PMID: 20977901 |
| Start Year | 2008 |
| Description | Using a Prx1 transgenic to study the periosteal stem cell niche |
| Organisation | UCB Pharma |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | My lab is contributing a unique reagent that we produced that enables a cell-type of interest in bone to be studied and isolated. My lab contributes expertise in embryogensis, genetic tools and genetic approaches and imaging analysis |
| Collaborator Contribution | Experise in bone biology, techniaues in bone biology and novel reagents for studying bone biology (particularly immuno therapy reagents and osteogenic bone matrices). A biopharma outlook on a biological and clinical probelm. |
| Impact | BBSRC-CASE studnetship awarded to a PhD student who I am hositng in my lab but who will also work directly with teams at UCB |
| Start Year | 2016 |
| Description | Wellcome consortium Phenotyping Mouse cKO |
| Organisation | The Wellcome Trust Sanger Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | Wellcome Trust Strategic Award 2012-2017 £5,000,000 "Deciphering the Mechanisms of Developmental disease" |
| Collaborator Contribution | Grant has been awarded but not started yet |
| Impact | Grant awarded but not yet started |
| Start Year | 2012 |
| Description | Advice to author David Nicholls |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | provided advice to author preparing a novel with main protagonist a scientist giving advice to author with very large audience to help produce a pro-science book that humanises the practice of science and demsytifies science and scientists to the general public |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.davidnichollswriter.com/ |
| Description | Contribution to TV programme |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Contributed to Channel 4 programme "Easter Eggs Live" providing facility and expertise to produce images of chicken and Emu embryos developing in ovo for a programme focused on explaining embryonic development (in ovo) to the general public Good interaction with programme producers. Tangible output and wide audience reached |
| Year(s) Of Engagement Activity | 2013 |
| URL | http://www.channel4.com/programmes/easter-eggs-live/4od |
| Description | Contribution to WHO meeting on Thalidomide embryopathy |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | Yes |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | WHO report published http://www.thalidomidetrust.org/thalidomide-embryopathy-world-health-organisation-report/ After my contribution I estyablihsed new links with workers/policy makers on Thalidomide embryopathy I have since given a presentation for the Thalidomide trust, been invited to write a report for Thalidomide trust and have established a collaboration with a Japanese group working on Thalidomide embryopathy |
| Year(s) Of Engagement Activity | 2014 |
| Description | Gave talk for "Pint of Science" festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Gave a talk (alongside a clinical collaborator, Bran Sivakumar) to general public describing the work we do to study the rogins of limb defects and improving clinical treatments |
| Year(s) Of Engagement Activity | 2016 |
| URL | https://pintofscience.co.uk/event/building-body-parts |
| Description | Genetics Society executive committee member |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | genetics Society committee meetings Genetics Society Executive meetings Interview panels for genetics Society Working group for Centenary celebrations Dealing with Genetics Society journals (Heredity and Genes and Development) Liason with publihsers Springer-Nature and CSHP genetics Society committee meeting |
| Year(s) Of Engagement Activity | 2013,2015,2016,2017 |
| URL | http://www.genetics.org.uk/ |
| Description | NIMR Open day |
| 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 | Public/other audiences |
| Results and Impact | 100 or so guests visited the NIMR to hear about the work that goes on at the MRC funded research institute http://www.nimr.mrc.ac.uk/news/nimr-open-day-impresses-visitors/ |
| Year(s) Of Engagement Activity | 2013 |
| URL | http://www.nimr.mrc.ac.uk/news/nimr-open-day-impresses-visitors/ |
| Description | Presentation for Thalidomide Trust UK |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | open new avenues for interactions Talk stimulated debate and future activities After the talk I was asked to provide advice to former chairman of Trust who is writing a book on origins of Thalidomide Also met potential collaborators for future work on Thalidomide causes and treatment |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.thalidomidetrust.org/public/national-advisory-council-nac/ |
| Description | SChoolls day NIMR |
| 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 | Local |
| Primary Audience | Schools |
| Results and Impact | Set-up and run a demonstration of chick embryogenesis to enable school children to observe and get hand-on experience of animal models used in research Always get good feedback and lots of questions from the students |
| Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012 |
| Description | School essay prize winner trip |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Give presentation and demonstration to school essay prize winners and explain what we do here at NIMR get positive feedback from students |
| Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012 |
| Description | University of Third Age |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | 180 attendees for regional U3A meeting at NIMR Good feedback from u3A. will continue collaboration with NIMR for annual meetings |
| Year(s) Of Engagement Activity | 2012 |
| Description | challenges in 3D bioprinting |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other academic audiences (collaborators, peers etc.) |
| Results and Impact | group of 50-100 discussiing challenges and potential for use of 3d bioprinting in development of translational/regenerative medicine. representation from various interest groups from biologists to chemist to engenineers, patent lawyers industrialists and funding agencies good networking and catalyst for future meeting to inspire interdisciplinary projects. |
| Year(s) Of Engagement Activity | 2013 |