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.
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.
People |
ORCID iD |
Sarah Bray (Principal Investigator) |
Publications

Babaoglan AB
(2013)
Deadpan contributes to the robustness of the notch response.
in PloS one

Krejcí A
(2009)
Direct Response to Notch Activation: Signaling Crosstalk and Incoherent Logic
in Science Signaling

Simón R
(2014)
Drosophila p53 controls Notch expression and balances apoptosis and proliferation.
in Apoptosis : an international journal on programmed cell death

Housden BE
(2012)
Drosophila Reporter Vectors Compatible with FC31 Integrase Transgenesis Techniques and Their Use to Generate New Notch Reporter Fly Lines.
in G3 (Bethesda, Md.)

Terriente-Felix A
(2013)
Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme.
in Development (Cambridge, England)

Pézeron G
(2014)
Notch directly regulates cell morphogenesis genes, Reck , talin and trio , in adult muscle progenitors
in Journal of Cell Science

Li J
(2014)
Notch signaling assays in Drosophila cultured cell lines.
in Methods in molecular biology (Clifton, N.J.)

Slaninova V
(2016)
Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle.
in Open biology

Bernard F
(2010)
Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors.
in Development (Cambridge, England)

Pines MK
(2010)
The cytolinker Pigs is a direct target and a negative regulator of Notch signalling.
in Development (Cambridge, England)
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 | 04/2008 |
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 | 04/2014 |
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 | 06/2006 |
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 | 04/2008 |
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 |