Genes involved in regulating and executing Notch function

Lead Research Organisation: University of Cambridge
Department Name: Anatomy

Abstract

When the communication-signals in our body fail, the cells may adopt the wrong structure or proliferate uncontolled, as occurs in cancer. One important means of communication is through the protein Notch, which is essential for the normal development of the body. Defective Notch proteins are also the cause of some cancers and are associated with a number of late onset diseases.

Recent sequence of human and Drosophila genomes suggests that over 2000 human disease genes are conserved in flies. The goal of our research is to take advantage of Drosophila (where Notch was first discovered) as a model, to find out which other genes are needed to successfully interpret the information that comes through Notch.

So-called genetic screens in Drosophila make it possible to sift through all the genes in the genome to find which ones are needed for Notch to work properly. We will confirm whether the same players are present in human genome, and will ask whether any of these contribute to known diseases.

Through the identification of new players and the development of new assays we aim to provide valuable tools for developing drugs or diagnostic assays, in cases where Notch is a potential target.

Technical Summary

Notch receptors are implicated in many different developmental and disease processes. First characterised through a role in neurogenesis, where it limits the numbers of cells that adopt neural fates, Notch signalling has subsequently been found to regulate a vast array of other events including somitogenesis, myogenesis, hematopoeisis, limb and retinal development. At the same time, inappropriate activation of Notch has been linked to several types of cancer, and mutations in Notch receptors and ligands are associated with diseases such as adult onset dementia. More recently it has become clear that the activation of Notch involves proteolysis by Presenilin, an enzyme that also cleaves Apolipoprotein and is affected in Alzheimer s. Thus, an understanding of Notchfunction will not only contribute to our understanding of development but will also be important in the context of treatments for cancer, Alzheimer s and related diseases. Although we have a framework for the Notch pathway, there remain many gaps in our understanding of how this important receptor is regulated and how its activity translates into biological functions. The goal of our programme is to use molecular, genetic and microarray approaches to identify genes involved in regulating and implementing Notch activity. In particular we wish to 1) dissect Notch-mediated effects on transcription by developing sophisticated cell culture assays; 2) identify novel genes that regulate or participate in Notch signalling using genetic modifier screens; 3)examine the spectrum of direct Notch target genes using microarray analysis coupled with bioinformatics; 4) determine how subcellular differences in cell polarity regulate Notch activation.

Publications

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publication icon
Bray SJ (2006) Notch signalling: a simple pathway becomes complex. in Nature reviews. Molecular cell biology

 
Description AICR Project Grant
Amount £40,637 (GBP)
Funding ID AICR-06-477 
Organisation Association for International Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 09/2009
 
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 Project Grant
Amount £261,000 (GBP)
Funding ID G0500926 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2006 
End 10/2009
 
Description Postdoctoral Fellowship to Fred Bernard
Amount £60,000 (GBP)
Funding ID ALTF 372-2007 
Organisation European Molecular Biology Organisation 
Sector Charity/Non Profit
Country Germany
Start 09/2007 
End 08/2009
 
Title Ectodomain shedding activation protocol 
Description Cell based method for activating Notch 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact helping to validate targets in cancer cells, still in test phase. 
 
Title In vivo NRE 
Description Reporter of Notch activity in vivo 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact multiple publications e.g. PMID: 17303754 PMID: 16340959 PMID: 18779369 PMID: 18284659 
URL http://europepmc.org/abstract/MED/17303754
 
Title NRE-reporter 
Description Notch reporter plasmid for Drosophila cells. For cell based assays of Notch activity, allows testing of other factors and regulators 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Used by researchers worldwide in test of novel Notch pathway components etc. e.g see PMID: 16256745; PMID: 25053486; PMID: 22384384 
URL http://europepmc.org/abstract/MED/16256745
 
Description Bowl and lines 
Organisation Autonomous University of Madrid
Department Centre for Molecular Biology Severo Ochoa
Country Spain 
Sector Academic/University 
PI Contribution developed reagents and contributed to the experimental design and analysis, hosted student in group for 2 visits, funded by Company of Biologists and by EMBO short term fellowship.
Collaborator Contribution Student from Madrid visited the lab and carried out key experiments, and contributed essential reagents and data. Co-authored publication
Impact PMID: 19270177
Start Year 2006
 
Description Notch Transcription Co-regulators 
Organisation Erasmus University Rotterdam
Country Netherlands 
Sector Academic/University 
PI Contribution We have an exciting collaboration with Peter Verrijzer in Erasmus to investigate the role of key chromatin factors in Notch regulation. Peter's lab is an expert in biochemistry and they have found potential co-regulators through these approaches. We then test function using biological assays, including in vivo models
Collaborator Contribution Contributed essential reagents and data Discussion of ideas and implications
Impact PMID:17925233 PMID:19782028
 
Description Notch targets 
Organisation Foundation for Research and Technology Hellas (FORTH)
Department Institute of Molecular Biology and Biotechnology (IMBB)
Country Greece 
Sector Academic/University 
PI Contribution Contributed essential data and reagents, discussions of data and co-authored papers
Collaborator Contribution Essential reagents and data Co-authored publications
Impact PMID: 17006545 PMID: 20040486
 
Description Leukemia Society sponsored conference, Notch signaling in Normal and malignant Hematopoiesis 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Miami. USA conference also included clinicians and policy makers

led to further conference invitations and collaborations
Year(s) Of Engagement Activity 2006
 
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 Talk and activities 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact classes of 8-year old children from neighbouring schools visited for talks and practical activities their feedback (via questions and web-pages) was very positive

children learned about medical research and encountered women in professional roles
Year(s) Of Engagement Activity 2007
 
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
 
Description WIMM: Institute Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Invited seminar at the MRC Molecular Hematology Unit, WIMM Oxford

sharing of data
Year(s) Of Engagement Activity 2006