Somites and patterning of the vertebral column

Lead Research Organisation: University College London
Department Name: Cell and Developmental Biology

Abstract

Malformations of the vertebral skeleton are very common in humans. As many as 10% of adolescent females may be affected by scoliosis, in addition to which there are many other musculo-skeletal problems of varying severity. We know very little about the causes of these anomalies, except that they are all due to some problem that happens during development of the cells that produce the vertebrae in the embryo. These cells are arranged into blocks, called somites. Deviations of the spine appear to be due to a local defect in somite size, for example affecting a somite on the left and not on the right. This project investigates the mechanisms that determine somite size and the rate at which they form. It also explores the relationship between the initial pattern of somites and the mature vertebrae that form from them. The results obtained will be very important for designing new diagnostics potential therapies.

Technical Summary

The vertebrae that make up the axial skeleton arise from blocks of mesodermal cells in the embryo, called somites. However we know very little about the mechanisms that regulate their size and spatial arrangement. Expression of a number of genes (mainly in the Notch pathway) cycles at the same rate as somite formation in pre-somitic cells, and it is thought that this ?segmentation clock? regulates the size of somites. However this has not been tested directly, and several observations suggest that this clock could function instead to specify of the identity of cells in the rostral and caudal halves of the somite. The first part of this project takes advantage of a new experimental paradigm to separate the rhythmicity of somite formation from segmentation itself and explore the effects on somite patterning. After somites form, it is also widely assumed that one somite contributes to two adjacent vertebrae by a process of ?re-segmentation?. Although this has been tested by several studies, none of them have proved conclusive. The second part of the project investigates this directly using novel fate mapping approaches. Finally, the third part of the project explores the possibility, suggested by recent results, that some of the instructions for patterning may arise from the notochord (which mainly contributes to the intervertebral nucleus pulposus).

Publications


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Dias AS (2014) Somites without a clock. in Science (New York, N.Y.)
Dias AS (2014) Somites without a clock. in Science (New York, N.Y.)
Stern CD (2015) Multiple roles of timing in somite formation. in Seminars in cell & developmental biology
Ward L (2017) A resegmentation-shift model for vertebral patterning. in Journal of anatomy
 
Description REF2014 - Sub-Panel 5A
Geographic Reach UK 
Policy Influence Type Participation in advisory committee
Impact membership of this sub-panel. Experience from this project contributed to my selection as panel member and to the discussions. Assessing quality of research from academic research institutions across the UK.
 
Description Saverio Ochoa Evaluation, Spain
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact Advisory/assessing applications of centres of excellence in Biomedical Sciences in Spain, for Ministery of Science and Innovation. Chosen as member largely because of research on this project.
 
Description Scienctific Council, Pasteur Institute
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact Advisory as member of council of the Pasteur Institute, Paris, France. Selected largely because of work on this project.
 
Description UKCMRI Scientific Planning Committee
Geographic Reach UK 
Policy Influence Type Membership of a guidance committee
Impact Planning of new Research Institute in St Pancras (Crick Institute) - experience from this research contributed to my experience and influenced contributions to the planning deliberations
 
Description UKCMRI Scientific Planning Committee (SPC)
Geographic Reach UK 
Policy Influence Type Participation in advisory committee
Impact planning science strategy UKCMRI new institute at St Pancras, London.
 
Description European Research Council (ERC)
Amount £1,800,000 (GBP)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 06/2010 
End 05/2015
 
Description NIH Research Grant (R01)
Amount $620,000 (USD)
Funding ID 2R01GM076692 
Organisation National Institutes of Health (NIH) 
Department National Institute of General Medical Sciences (NIGMS)
Sector Public
Country United States of America
Start 11/2012 
End 11/2016
 
Title Improved grafting methods 
Description Improved method for grafting Hensen's node 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact PMID: 19030803 
URL http://europepmc.org/abstract/MED/19030803
 
Title Improved grafting methods (2) 
Description Improved grafting methods for primitive streak stage embryos 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact PMID: 18485289 
URL http://europepmc.org/abstract/MED/18485289
 
Description Joint research 
Organisation School of Biological Sciences Cambridge
Department Department of Physiology, Development and Neuroscience
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution joint research
Collaborator Contribution joint research experiments
Impact still on-going project. Likely to lead to at least one published output next year.
Start Year 2009
 
Description Modelling of somite formation 
Organisation Indiana University
Department Biocomplexity Institute
Country United States of America 
Sector Academic/University 
PI Contribution Collecting and providing experimental data to build and test mathematical and computational models of vertebral column development and to predict new genes involved involved in human disease.
Collaborator Contribution New collaboration, expected to bring new funding (results of application will be available in July 2012)
Impact Collaboration on a joint project to model somite formation based on results directly arising from this project. Placed an application for funding from NIH in 2011 for this.
Start Year 2011