Department of Physiology, Development and Neuroscience

• University of Cambridge
• School of the Biological Sciences
• Department of PDN
• Academic Staff

Professor of Developmental Biology Tel: +44 (0)1223 333792, Fax: +44 (0)1223 333786, E-mail: sjb32@cam.ac.uk

From stem cells to tissues: Notch regulatory networks in development

The Notch pathway is one of a small handful of cell signalling pathways that coordinate animal development, regulating the types and numbers of cells formed in many developmental contexts. Its roles include the maintenance of stem cell/progenitor populations, a requirement that continues during tissue homeostasis in the adult. Aberrant Notch function is also implicated in many diseases including dementia and many cancers. Elucidating how Notch signalling functions in different contexts is thus not only vital for understanding development but also has the potential to identify novel markers to aid treatments for human diseases.

Despite the relative simplicity of its transduction pathway, the consequences of activating Notch differ significantly according to the cell context. This is powerfully illustrated by the diverse developmental outcomes specified by Notch (e.g. stem cell maintenance, progenitor selection, growth organising boundaries) and by the fact that Notch promotes tumour growth in some circumstances but prevents it in others. Although we are aware of these different consequences, we know little of how they come about. For example, can Notch exert its effects by acting on a small number of genes, that in turn feed forward to regulate many others, or does it, in the extreme case, regulate a large number that are all needed to change cell behaviours? How similar are the sets of genes turned on by Notch in different contexts? These are some of the questions we are addressing through our genome-wide studies of Notch target genes.

We primarily use Drosophila as our model, due to the powerful genetics that allow us to directly test the in vivo importance of novel components and targets. Furthermore, its small genome size facilitates our genome-wide investigations into Notch targets. The extent of conservation with humans (~80% of human disease genes have orthologues in Drosophila) has been emphasised by our identification of genes clearly relevant to human cancers amongst the Notch targets from our Drosophila studies.

Our first genome-wide experiments focussed on muscle progenitors where we have found 125 targets involved in the maintenance of adult myogenic precursors, including many novel genes whose function we are characterizing. We are now decoding our results from a second cell type, related to blood cells, where we find some overlapping and some novel targets. In both cases we find many examples of “incoherent feed-forward loops”, where Notch stimulates the expression both a gene and the repressor of that gene. This may result in a transient window of competence following Notch activation, and has made us interested in the temporal profile of the response.

Current projects focus on:

1. the developmental functions of novel targets indentified in our genome-wide screens
2. following through cohorts of genes, to understand how Notch regulates specific processes (e.g. progenitor maintenance)
3. further genome wide-studies to elucidate the response in different cell types and how the response changes with time
4. finding out the genetic and epigenetic mechanisms responsible for conferring different responses

Overview of the Drosophila X-chromosome showing sites of Su(H) binding (blue) in muscle progenitor-related cells.(Black boxes depict genes; red graphs indicate positions with sequence matches to Su(H) binding sites)

Current Lab Members 

• Burcu Babaoglan
• Alex Djiane (Post Doctoral Fellow)
• Guillaume Pezeron (Post Doctoral Fellow, EU Marie Curie)
• Silvie Fexova (PhD student, BBSRC and Cambridge Trusts)
• Audrey Fu (Post-doctoral Fellow)
• Jinhua Li (PhD student, CSC Cambridge Scholarship
• Kat Millen (Lab Manager)
• Ana Terriente-Felix (Post-doctoral Fellow)

Current Collaborators

• Dr Steve Russell (Systems Biology, Cambridge)
• Prof Simon Tavare (DAMTP, Cambridge)
• Dr Peter Verrijzer (Erasmus University, Rotterdam)
• Dr Christos Delidakis (IMBB, Crete)
• Dr Boris Adryan, (Systems Biology, Cambridge)

Main sources of funding: MRC, BBSRC, Wellcome Trust

Selected Recent Publications

Djiane A, Shimizu H, Wilkin M, Mazleyrat S, Jennings MD, Avis J, Bray S*, Baron M*. (2011) Su(dx) E3 ubiquitin ligase-dependent and -independent functions of Polychaetoid, the Drosophila ZO-1 homologue. J Cell Biol. 192:189-200

Bernard, F, Krejci, A, Housden, B, Adryan, B and Bray, SJ (2010) Specificity of Notch pathway activation: Twist controls the transcriptional output in adult muscle progenitors. Development 137(16): 2633-42.

Pines, MK, Housden, BE, Bernard, F, Bray, SJ and Röper, K. (2010) The cytolinker Pigs is a direct target and a negative regulator of Notch signalling. Development 137(6): 913-22.

Bray, SJ and Bernard, F. (2010) Notch targets and their regulation. Current Topics in Developmental Biology 92: 253-75.

Moshkin YM, Kan TW, Goodfellow H, Bezstarosti K, Maeda RK, Pilyugin M, Karch F, Bray SJ, Demmers JAA and Verrijzer CP. (2009) Histone Chaperones ASF1 and NAP1 Differentially Modulate Removal of Active Histone Marks by LID-RPD3 Complexes during NOTCH Silencing. Molecular Cell 35(6): 782-93.

Krejci A, Bernard F, Housden BE, Collins S, Bray SJ (2009) Direct Response to Notch Activation: Signaling Crosstalk and Incoherent Logic. Science Signaling 2, ra1. ( Summary, Abstract, Full Text)

Bray SJ, Takada S, Harrison E, Shen SC, Ferguson-Smith AC. (2008) The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila. BMC Dev Biol. 8:11.

Narasimha, M., Uv, A., Krejci, A., Brown, N. H., and Bray, S.J. (2008) Grainyhead promotes expression of septate junction proteins and influences epithelial morphogenesis. Journal of Cell Science 121, 747-52.

Goodfellow, H., Krejci, A., Moshkin, Y., Verrijzer, C.P., Karch,F. and Bray S.J. (2007) Gene-Specific Targeting of the Histone Chaperone Asf1 to Mediate Silencing. Developmental Cell 13, 593-600.

Krejci, A and Bray, S.J. (2007) Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes and Development 21,1322-7.

Glittenberg, M., Pitsouli, C., Garvey, C., Delidakis, C. and Bray S.J. (2006) Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis. EMBO Journal 25(20):4697-706

Bray, S.J. (2006) Notch Signalling: a simple pathway becomes complex. Nature Reviews in Molecular Cell Biology 7, 678-689.

Bray S.J., Musisi, H. and Bienz, M. (2005) Bre1 is required for Notch signalling and histone modification. Developmental Cell 8, 279-86.

Almeida, M and Bray S.J. (2005) Regulation of Post-embryonic Neuroblasts by Drosophila Grainyhead. Mechanisms of Development 122, 1282-93

Nagel, A.C., Krejci, A., Tenin G., Bravo-Patiño A., Bray, S.J., Maier, D., and Preiss, A. (2005) Hairless mediated repression of Notch target genes requires combined activity of Groucho and CtBP co-repressors. Molecular and Cellular Biology 25, 10433-10441

Perez, L., Milan, M., Bray, S.J. and Cohen, S. (2005) Ligand binding and signaling properties of the Abruptex[M1] mutant form of Notch. Mechanisms of Development 122, 479-86.