Decoding the Notch signal

Lead Research Organisation: University of Cambridge
Department Name: Physiology Development and Neuroscience

Abstract

The human body is composed of millions of cells which have to be assembled and maintained correctly. For this complex assembly process to happen, the cells need to communicate with each other. They do so via special types of signals. One such signal uses a protein called Notch as its receiver. Messages sent through Notch can make cells proliferate or change their behaviours, and sometimes even die. What we don?t understand is how Notch can communicate such different messages at different times. This is of major importance because we now know that inappropriate activity of Notch is responsible for several types of cancers and is linked to other disease too. The goal of our work is to understand the language of the different messages that Notch sends at different times and to identify particular ?signatures? that will be helpful in clinical situations to show whether Notch is working inappropriately. If it is, this may influence what treatments should be provided. In addition, the ?letters? within a signature could give us good clues about ways to develop new drugs for particular cancers in future.

We do most of our experiments using the fruitfly, which gives us a simpler model to decode these different messages. Because there are very big similarities between the ways cells work in flies and people (Notch was first found in fly studies and ~80% of disease causing genes can be found in flies) we are confident that the fly experiments will give us a route to important tools for use in the clinic.

Technical Summary

Signalling through the Notch receptor controls many different decisions in development, contributes to the maintenance of tissues in the adult and is associated with a number of diseases, including cancers. Despite its simple transduction pathway, Notch activation elicits different consequences in these different contexts, for example sometimes causing proliferation, sometimes cell-death. Our goal is to investigate the molecular basis for this diversity. Through a combination of genomic and genetic approaches, primarily using Drosophila as our model, we aim (I) to discover the relevance of novel Notch targets in development and disease (II) to investigate the diversity of responses in different tissues; (III) to determine mechanisms that cause different types of target-genes to be activated in different contexts. Together these studies will make a major contribution to our understanding of the differential consequences of activating Notch and, given the conservation between flies and humans, are likely to uncover new markers or mechanisms of regulation that could prove valuable for clinical use and intervention.

Publications

10 25 50
 
Description Chairman of Scientific Advisory Board, Action Medical Research
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact improved educational and skill level of the work-force
 
Description Career re-entry Fellowship for Sara Morais Da Silva
Amount £446,000 (GBP)
Funding ID 107414/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 09/2019
 
Description EMBO Short term fellowship
Amount £3,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 07/2010 
End 09/2010
 
Description MRC Programme Grant (Programming)
Amount £1,669,548 (GBP)
Funding ID MR/L007177/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2014 
End 04/2019
 
Description Post-doctoral Fellowship for Hadi Boukhatmi
Amount £56,000 (GBP)
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 10/2013 
End 09/2015
 
Description Project Grant (Mechanisms of gene regulation by CSL-Notch)
Amount £842,000 (GBP)
Funding ID BB/J008842/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2012 
End 05/2015
 
Description Royal Society Travelling Grant
Amount £4,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 12/2010
 
Title Fluorescent reporter vectors 
Description A series of vectors for assay functions of DNA enhancer elements in transgenic flies. Paper reporting the vectors is in press. 
Type Of Material Technology assay or reagent 
Year Produced 2011 
Provided To Others? Yes  
Impact PMID: 22384384; PMID: 25053484; ID: 2-s2.0-84901832561 
 
Title Notch reporter flies 
Description Series of transgenic fly lines for monitoring activity of the Notch pathway 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact are being made available this month 
 
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
 
Title Notch targets in hyperplasia 
Description Results from genome-wide expression profiling and chromatin immunoprecipitation 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact PMID:23232763 Data publicly available in GEO 
 
Title Genome-wide Changes in RNA expression levels, CSL binding profiles and Pol II occupancy over time course 
Description Expression arrays were used to measure the levels of mRNA in cells after notch stimulation Genomic tiling arrays were used to emasure CSL binding and Polymerse II binding over the same time-course. Data has been submitted to GEO. GEO Series record GSE35557 
Type Of Material Database/Collection of data 
Year Produced 2012 
Provided To Others? No  
Impact No actual impacts realised to date 
URL http://GEO http://www.ncbi.nlm.nih.gov/geo/
 
Title Genomewide changes in RNA and CSL binding in tumour models 
Description Data collection from profiling hyperproliferative tissues 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact data is available for mining 
 
Description Cux1 and other genes associated with blood tumors 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Screening functional relevance of candidate genes
Collaborator Contribution identified the candidate genes, analyzed sequence data from tumour samples
Impact Paper in press in Nature Genetics
Start Year 2012
 
Description Epigenetic regulation of T-Reg Cells 
Organisation University of Cambridge
Department Department of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed to experimental design, provided training for researchers,
Collaborator Contribution Partners carried out the experiments and analyzed the data
Impact Research paper published Training contributed to career progression of David Bending, now has independent fellowship
Start Year 2009
 
Description Hamlet 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution Experimental design and strategy, data interpretation. Performed some of the key experiments and made important discovery
Collaborator Contribution Intellectual concepts that have informed our subsequent research directions
Impact Paper in press in Nature Neuroscience Endo K, Karim MR, Taniguchi H, Krejci K, Kinameri E, Siebert M, Ito K, Bray SJ and Moore AW. (2012) Olfactory receptor neuron identity is diversified by the Drosophila Evi1/Prdm16 Homologue Hamlet that mediates chromatin modification at Notch-target loci. Nature Neuroscience in press
Start Year 2008
 
Description Mechanisms of Notch regulated transcription: a proteomics approach 
Organisation Erasmus University Rotterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Bray Group contributed the biological framework and specific antibodies relevant for Notch complexes
Collaborator Contribution Provided expertise and resources for proteomics analysis of Notch complexes. Hosted Prof Bray for sabbatical visit
Impact Royal Society Travelling Grant for Sarah Bray
Start Year 2010
 
Description Modelling transcription factor binding 
Organisation University of Cambridge
Department Cambridge Systems Biology Centre (CSBC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Giving the mathematician modeller RZ opportunity to participate in laboratory research for training. Experiments are performed in our lab under supervision of a post-doc and will provide data from his modelling. Funded by MRC Centenary Award.
Collaborator Contribution Mathematical modelling
Impact Collaboration was initiated in Oct 2012. No tangible outputs yet apart from training. It is multidisciplinary: involves molecular biology, genomics and computational modelling
Start Year 2012
 
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 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 targets in neuroblasts 
Organisation Foundation for Research and Technology Hellas (FORTH)
Department Institute of Molecular Biology and Biotechnology (IMBB)
Country Greece 
Sector Academic/University 
PI Contribution Provided the expertise and resources for analysis of Notch targets in neuroblasts
Collaborator Contribution Provided samples for the study
Impact EMBO Short term fellowship for Evanthia Zacharioudaki Notch targets in neuroblasts, data will be cross-referenced and integrated with other data sets we have generated.
Start Year 2010
 
Description Danstem 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at Danstem, involves scientists and practitioners
Year(s) Of Engagement Activity 2014