Direct targets of Notch signalling activity

Lead Research Organisation: University of Cambridge
Department Name: Anatomy

Abstract

For cells in the body to know what tissue they are part of, whether to grow, they need to communicate. The Notch receptor is central to one communication pathway and is essential for our bodies to be made with the right number and types of cell. It is also important throughout our lives because overactive Notch receptors are the cause of some cancers and defective Notch causes other diseases including types of dementia.
In each cell-type in the body, only a small fraction of our genes are turned on. When Notch is active it results in additional genes being turned on. We are aiming to find out the identity of these additional genes and to investigate whether this can help us understand why Notch causes cells to change their behaviour and become cancerous.
Our model is the fruit-fly Drosophila melanogaster, where Notch was first identified. Recent sequence of human and Drosophila genomes shows that over 2000 human disease genes are conserved in flies. As Drosophila has fewer genes, fewer cells and is easy to work with, it provides a good starting-point to identify genes that are important in cancers and that could be important therapeutic targets.

Technical Summary

Intercellular signalling via the Notch pathway is essential at many steps in the development of an animal as well as during post-natal life. Furthermore, correct regulation of this pathway is crucial, since aberrant Notch activity is associated with many types of human diseases including delayed onset dementia and cancers. Although it is clear that the changes in cell behaviour elicited by Notch activation involve rapid alterations in gene expression, very few genes controlled by Notch have been characterised to date. The overall aim of our proposal is to discover how Notch signalling leads to specific changes in cell behaviour by identifying the genes that are activated in different cell types and assessing how they contribute to the Notch response. Using Drosophila as a model we will: 1) use microarray approaches to systematically identify new Notch target genes, 2) validate these genes as Notch targets within the developing animal 3) study the developmental and biological function of a selected set of target genes, focussing on their contribution to Notch mediated processes and testing their conservation in mouse. Identification of such targets will be vital for understanding different functions of Notch during development and in human diseases.

Publications

10 25 50
 
Description BBSRC Project Grant (The dynamics of gene regulatory networks induced by Notch activation)
Amount £632,406 (GBP)
Funding ID BB/F00897X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2008 
End 04/2011
 
Description MRC Programme Grant
Amount £1,629,570 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2008 
End 12/2014
 
Description MRC Programme Grant (Programming)
Amount £1,669,548 (GBP)
Funding ID MR/L007177/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2014 
End 04/2019
 
Description Post Doctoral Fellowship for Guillaume Pezeron
Amount £95,000 (GBP)
Funding ID IEF-236426 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2006 
End 06/2011
 
Description Wellcome Trust Project Grant (Cross-talk between Notch and TNF signalling pathways: role of dTraf1)
Amount £173,569 (GBP)
Funding ID WT083576MF 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2008 
End 08/2011
 
Title Notch targets 
Description direct Notch targets regulated in muscle progenitor cells through gene expression and chromatin immunoprecipitation 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact PMID:19176515 
URL http://europepmc.org/abstract/MED/19176515
 
Description Notch targets in cancer 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided enabling data from our research, provided technical assistance and training
Collaborator Contribution comparisons with clinical array data
Impact helped train clinical fellow in molecular techniques likely to yield future publications contributed to proposal for G0800034
Start Year 2007
 
Description Notch and cancer Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Focussed meeting on Notch and cancer. Brought together basc and clinicians

discussions pending re EU grant application
Year(s) Of Engagement Activity 2008
 
Description The Notch Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Conference brought together non-clinical and clinical researchers in the field of Notch signaling

Postdoctoral applications to my lab Invitations to subsequent conferences
Year(s) Of Engagement Activity 2007