Vertebrate embryonic development

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

We are interested in the way in which the spinal cord develops in embryos. The spinal cord is a bundle of different types of nerves - some controlling muscle movement (motor neurons) and some receiving sensation from the skin (sensory neurons). These different types of nerve cells grow at different positions in the spine and the arrangement of nerves in the spine is crucial for its proper function. This special pattern of nerve types is dictated by a set of genes. Recently, using chick and mice embryos we identified some of the genes that tell cells to become motor neurons. Like most genes, the genes that control motor neurons are found in all cells of the body, but they are not always active. Instead, they are turned on and off in a strict pattern according to which cells they are in and we now wish to study this process. This will increase our understanding of the way in which the motor neurons are formed. This information could enable us to grow new motor neurons in the lab, potentially offering hope to people with spinal injuries or motor neuron disease. It is also likely that similar processes will be involved in controlling other aspects of embryo development - in the skin, limbs and brain for instance. This research could therefore shed new light on a number of congenital birth defects as well as diseases such as skin cancer and brain tumours.

Technical Summary

We are investigating the molecular mechanisms that control the correct formation and positioning of different nerve cell types in the spinal cord of vertebrates. The assembly of functional neuronal circuits begins in vertebrates with the generation of distinct classes of neurons at defined positions. We have focused on the ventral neural tube, the region of the spinal cord that contains motor neurons and other neuron types that control and coordinate motor output, these neurons allow us to do such things as move our limbs, breath and swallow. Our goal is to understand the molecular mechanisms controlling the pattern in which these distinct neuronal subtypes are generated. An understanding of these processes will have implications for diseases such as motor neuron disease as well as tumours of the nervous system. We have shown that a signalling molecule, Sonic Hedgehog (Shh), plays a central role. Shh is secreted by a defined group of cells at the midline of the neural tube and acts directly on neural cells throughout the ventral neural tube. Shh signalling controls, in a concentration dependent manner, the expression of a group of homeodomain proteins in neural progenitors. The combinatorial expression of these homeodomain proteins establishes five distinct domains of progenitors. Homeodomain proteins expressed in adjacent domains cross-repress each others expression refining and maintaining progenitor domains and, as cells differentiate, the homeodomain proteins expressed in a progenitor domain direct neuronal subtype identity. While these data begin to reveal the genetic networks that interpret Shh signalling to control neuronal fates, the way in which the graded activity of Shh signals intracellularly to control gene expression is poorly understood. The control of differential gene expression by a graded signal is a central question in developmental biology and similar issues have arisen from the study of the development of other embryonic tissues. To address this problem in the neural tube, we are taking a combination of molecular, cellular and embryological approaches. Using in vivo transgenic methods in mouse and chick embryos, we are examining how components of the Shh signalling pathway including Shh regulated transcription factors control gene expression. Conversely, we are identifying the DNA elements necessary to control Shh regulated genes. In parallel we are developing Shh responsive cell lines to allow the in vitro characterisation of Shh signalling. These approaches together with the reagents available and the level of knowledge we have of the developing nervous system should allow us to provide answers to how a graded signal regulates gene expression. In addition, Shh signalling is important in the development of other tissues, including limbs and the skin, it is likely therefore that this research will increase our understanding of a number of congenital birth defects as well as cancers such as basal cell carcinoma and medulloblastoma. Graded Shh signalling alone is not sufficient to account for the variety of neuronal subtypes generated in the ventral neural tube, indicating that additional mechanisms increase neuronal diversity. Using the strategy of examining candidate regulators and target genes we are analysing situations in which mechanisms other than Shh signalling must play a role in specifying neuronal subtype identity. Together, these approaches will provide an understanding of the mechanisms controlling neural tube development.

Publications

10 25 50
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Ashe HL (2006) The interpretation of morphogen gradients. in Development (Cambridge, England)

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Bardet PL (2008) A fluorescent reporter of caspase activity for live imaging. in Proceedings of the National Academy of Sciences of the United States of America

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Briscoe J (2008) Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Briscoe J (2006) Agonizing hedgehog. in Nature chemical biology

 
Description Roslin Institute
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description Autism Speaks (Formerly NAAR) award 2006
Amount £31,950 (GBP)
Organisation Autistica 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2006 
End 09/2007
 
Description EU- Marie Curie- Intra-European Fellowship
Amount £154,702 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 02/2010 
End 01/2012
 
Description EU- Marie Curie- Intra-European Fellowship
Amount £146,680 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 05/2011 
End 04/2013
 
Description EU-Marie Curie Intra-European Fellowship
Amount £113,949 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 07/2006 
End 06/2008
 
Description EU-Marie Curie-International Incoming Fellowship
Amount £149,225 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 08/2008 
End 08/2010
 
Description Simons Foundation
Amount £157,000 (GBP)
Organisation Simons Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2012 
End 12/2013
 
Description Wellcome Trust Grant
Amount £173,324 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2008 
End 06/2011
 
Description Wellcome Trust Grant
Amount £287,805 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 02/2011
 
Title Visgenex 
Description Software to visualize and analyse gene expression data from transcriptomic studies 
Type Of Material Data analysis technique 
Year Produced 2011 
Provided To Others? Yes  
Impact Puiblications 
 
Description Chris Watkins 
Organisation Royal Holloway, University of London
Department Department of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration between machine learning computer scientist at RHUL and our group
Collaborator Contribution Collaborative work
Impact Collaborative work resulting in a submitted paper
Start Year 2009
 
Description Elisa Marti 
Organisation Spanish National Research Council (CSIC)
Country European Union (EU) 
Sector Public 
PI Contribution Collborative project
Collaborator Contribution Joint project
Impact 16410413
 
Description JP 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Collaborative work
Collaborator Contribution Joint work
Impact 18779587
 
Description Karen Page 
Organisation University College London
Department Mathematics
Country United Kingdom 
Sector Academic/University 
PI Contribution Collobaration between mathematicians at UCL and our group
Collaborator Contribution Collaborative work
Impact Collaborative work resulting in a submitted paper
Start Year 2007
 
Description Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Interview with popular Portugese Science Magazine: Ciência Hoje - www.cienciahoje.pt

N/A
Year(s) Of Engagement Activity 2008
 
Description News release 
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 Media (as a channel to the public)
Results and Impact Press release that was picked up be several outlets including The Independent newspaper

none
Year(s) Of Engagement Activity 2014
URL http://www.independent.co.uk/news/science/breakthrough-in-spinal-cord-research-could-lead-to-eventua...
 
Description Popular essay 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Essay for the Mill Hill Essays series: http://www.nimr.mrc.ac.uk/millhillessays/2008/lastory/

n/a
Year(s) Of Engagement Activity 2008