IMPC: Analysis of the novel craniocardiac malformation gene Rapgef5
Lead Research Organisation:
King's College London
Department Name: Craniofacial Dev and Stem Cell Biology
Abstract
Birth defects are the major cause of infant mortality in the UK and in Europe. Of these, congenital craniofacial and cardiac malformations are amongst the most common with heart anomalies as the leading cause of infant mortality and morbidity. If we are to improve patient well being, we must identify and understand the genetic causes of birth defects as a critical first step towards improved screening, genetic counselling and personalised treatment strategies. Having identified human RAPGEF5 in patients with heart anomalies, we now need to establish a mammalian model, in order to better understand the underlying biological roles for the gene. This pump-priming project will establish an IMPC-generated mouse model Rapgef5. In addition to its role as a birth defect gene, Rapgef5 also seems to be important in the Wnt signalling pathway, which is associated with aging, and with disorders such as cancer and neurodegeneration. Therefore, establishment of this mouse model may provide us with a tool to understand human birth defects as well as important signalling processes that occur in human disease.
Technical Summary
RAPGEF5 is a newly identified candidate birth defect gene, originally identified in a heterotaxy patient. Heterotaxy is a disorder of left-right development and is associated with a severe subset of congenital heart anomalies. Previous data using the frog Xenopus confirmed a requirement for RAPGEF5 in LR development, organ situs and craniofacial development. Establishing a regulator of nuclear accumulation of beta-catenin would transform our understanding of the Wnt pathway and facilitate the development of treatments for diseases such as cancer and cardiac ischemia. In order to investigate this promising congenital disease gene, we need to build on our work by using mammalian systems, which better represent human genetics, development and cardiac anatomy. In particular, we take advantage of powerful murine genetics and state of the art cell culture techniques and reagents available in the lab. We anticipate that this project will provide us with the tools to understand the role of RAPGEF5 in development as well as the biochemical role of RAPGEF5 and associated RAP proteins in signal transduction.
Publications
Onesto V
(2019)
A quantitative approach for determining the role of geometrical constraints when shaping mesenchymal condensations.
in Biomedical microdevices
Alharatani R
(2019)
Expression of the guanine nucleotide exchange factor, RAPGEF5, during mouse and human embryogenesis.
in Gene expression patterns : GEP
Barrell WB
(2019)
Induction of Neural Crest Stem Cells From Bardet-Biedl Syndrome Patient Derived hiPSCs.
in Frontiers in molecular neuroscience
Griffin JN
(2018)
RAPGEF5 Regulates Nuclear Translocation of ß-Catenin.
in Developmental cell
Description | Horizon2020-EU International Training Grant, NEUCrest |
Organisation | Curie Institute Paris (Institut Curie) |
Country | France |
Sector | Academic/University |
PI Contribution | This project builds upon some of the studies begun in the BHF grant, mainly focusing on cranio-cardiac anomalies. |
Collaborator Contribution | The neural crest (NC) lineage is a specialised multipotent embryonic tissue, which contributes notably to the development of the human peripheral and enteric nervous system, craniofacial structures, pigment cells, as well as many other tissues and organs. Neurocristopathies, diseases of NC-derived tissues are an acute societal problem. The aim of the NEUcrest project is to train 15 creative and innovative PhD students within a novel, ambitious and interdisciplinary research program. This network is aimed at considering the overall genetic, molecular and epigenetic regulation of the NC tissue in human health. It involves 11 main interacting participants and 9 associated partners, from hospitals, academic laboratories and small and medium-sized enterprises, from 7 European or EU-associated countries: France, Ireland, Spain, The Netherlands, United Kingdom, Austria and Israel. Their cumulative expertise will provide an exceptional environment for PhD students, both for excellent research training and multiple transferable skills. This will allow the PhD students optimal career development and employability, through their acquired expertise in manipulating cells and embryos in various animal models, analysing biological images and datasets, and modelling complex genetic interactions. |
Impact | With an exceptionally rich training environment and regular network-wide events, our aim is to train 15 PhD students to be part of the next generation of leading European young scientists, highly proficient in the multidisciplinary range of scientific skills and technological expertise required for a comprehensive view of development and diseases : developmental and stem cell biology, cell and molecular biology, cancer biology, imaging, bioinformatics, human and animal genetics, and drug screening. In addition to the excellent doctoral training that each beneficiary will follow at his/her University, the network will provide an active training environment, by bringing together selected partners from the academic, industrial and communication sectors, and will stimulate fruitful interactions between the NEUcrest PhD students themselves through regular network-wide events. There will also be a strong emphasis on communication skills and public/patient/clinician outreach. Thus, the NEUcrest ITN will enable the selected PhD students to master scientific and transferable competences indispensable for addressing complex questions in Life Sciences and Human Health, and position them for leading roles in European academia and industry. |
Start Year | 2019 |