Vertebrate Limb Development 2
Lead Research Organisation:
King's College London
Department Name: UNLISTED
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
- King's College London (Lead Research Organisation)
- Guy's Hospital (Collaboration)
- Guy's and St Thomas' NHS Foundation Trust (Collaboration)
- Royal Free London NHS Foundation Trust (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- UCB Pharma (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- Great Ormond Street Hospital Children's Charity (GOSHCC) (Collaboration)
People |
ORCID iD |
Malcolm Logan (Principal Investigator) |
Publications
Booker BM
(2016)
Bat Accelerated Regions Identify a Bat Forelimb Specific Enhancer in the HoxD Locus.
in PLoS genetics
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
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 Paddy Hartley |
Description | We collaborated with artist Paddy to help him develop his biosculpture project "Papaver rhoeas" http://paddyhartley.com/papaver-rhoeas-2/ These series of exhibits encourage reflection on the meaning and use of remembrance, drawing particularly on the use and symbolism of the poppy in commemorating wars and war dead. This resulted in several exhibitions at the end of 2015 and further exhibitions are scheduled for 2016. http://paddyhartley.com/ |
Type Of Art | Artwork |
Year Produced | 2015 |
Impact | several exhibitions at the end of 2015 and further exhibitions are scheduled for 2016. http://paddyhartley.com/ |
URL | http://paddyhartley.com/papaver-rhoeas-2/ |
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 | Vice president corporate affairs, Genetics Society |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | BBSRC-CASE Studentship 4yr |
Amount | £122,104 (GBP) |
Organisation | UCB Pharma |
Sector | Private |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2020 |
Description | PhD studentship funding for clinical fellow (speciality in plastic surgery of limbs) in lab |
Amount | £100,000 (GBP) |
Organisation | British Society for Surgery of the Hand (BSSH) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2019 |
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 | 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 |
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 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 Helen Pilcher for her book "Bring back the King-The science of de-extinction" |
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 | Gave advice to author Helen Pilcher as she was preparing her book |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.bloomsbury.com/author/helen-pilcher |
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 National Gallery activity packs |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Invited to contribute to development of the National Gallery's children's activity packs. In particular scientific advice on development of ideas of encourage children to look at paintings in different ways and see the science under the paintings |
Year(s) Of Engagement Activity | 2015 |
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 | 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/ |