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Systems Biology of Notch Signaling
Introduction
The body plan of multicellular organisms is encoded by their genome. This blue print is used to shape the organism during its development from a single fertilized egg. It is remarkable, though, that despite the diversity in terms of shape and size, the number of genes and the gene sequence itself are quite similar between the different organisms. One of the main reasons for this phenomenon are the almost identical basic cellular processes which are used in all organisms, and that it is mainly the control in space and time when these processes are activated during development, which leads to the very different outcomes. For instance, the coordination of cellular proliferation and cellular differentiation relies on almost identical signaling pathways in Drosophila melanogaster and humans. One pathway of particular importance in this respect is the Notch signaling pathway. However, due to the complexity of these processes their detailed understanding was inaccessible to researchers for a long time. This changed with the introduction of large-scale mutagenic screens and the linking of mutant phenotypes with molecular and cellular actions in the model organism Drosophila.
The Notch signaling pathway is named after a X-linked dominant mutation, which was isolated in Drosophila by Dexter in the year 1914. The mutation exhibited early lethality and the haplo-insufficiency produced irregular tissue loss (notches) at the distal tip of the wing blade (Mohr, 1919; Morgan and Bridges, 1916). The fist evidence for the role of Notch as an important developmental cue was identified only later, when a complete loss of the Notch gene due to a deficiency produced lethal embryos with hyperplastic nervous system (Paulson, 1940). Another four decades later the Drosophila Notch gene was cloned (Artavanis-Tsakonas et al., 1983) and with time it became apparent that Notch governs one of the best-conserved signal transduction pathways required for metazoan development. In humans, Notch plays a fundamental role in cellular differentiation and stem cell biology and has been linked to a variety of diseases including cancer. The cloning of the Notch transmembrane receptor was followed by the identification of a rather simplistic pathway design: Activation of Notch by the binding of its ligands Delta or Serrate/Jagged leads to proteolysis of the receptor and the release of the intracellular domain, which engages in transcriptional regulation. However, several factors have been identified meanwhile, pinpointing to a complicated circuitry of control mechanisms mainly regulating maturation, endocytosis and degradation of the receptor and its ligands.
Genome-wide analysis of Notch pathway regulation
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In the past, single candidate gene approaches as well as very labor-intense large-scale genetic screens in Drosophila contributed significantly to the understanding of the Notch pathway and its control circuitries, and identified 161 interactors so far. However, it becomes more and more apparent that these approaches are insufficient, especially if it comes to understand the contributions of Notch signaling to disease. In this respect, the seemingly endless possibilities in altered gene activity levels, which can be found in human cancers and which can directly or indirectly contribute to changes in the output of the pathway, are a mayor challenge. Therefore, we decided to apply a Systems Biology approach to systematically identify all the components of the Notch signaling pathway, the underlying control circuitries, and the connections to other pathways in the model organism Drosophila. To this end we are using high-throughput RNAi screening techniques in combination with large-scale validation methods as well as proteomic approaches. The goal is the generation of a highly validated and mostly complete interaction network visualizing the Notch signaling pathway. The interdisciplinary nature of these approaches are highlighted by close interactions with the Computational Biology Group, which already culminated in a shared iPhD project funded by the Swiss SystemsX initiative. In a recent publication in Developmental Cell we are describing a first set of 353 validated novel Notch regulators we identified with a combination of high-throughput whole-genome ex vivo and in vivo RNAi screening techniques, and network analyses. With this data basis, and by the inclusion of new technologies and ideas, we plan to expand this Notch interaction network substantially and to link the Notch signaling cascade to selective target gene expression and growth control. |
People Involved
Dr. Abil Saj
Satbir Gill Kaur
Denise Stempfle
Enikő Molinár
Dr. Alexander Schwahn
Dr. Gunter Merdes
References
Stempfle, D., Kanwar, R., Loewer, A., Fortini, ME., and Merdes, G.
In vivo reconstitution of γ-Secretase in Drosophila results in substrate specificity.
Molecular and Cellular Biology 2010 Jul; 30(13):3165-3175. (PubMed).
Saj, A., Arziman, Z., Stempfle, D., van Belle, W., Sauder, U., Horn, T., Dürrenberger, M., Paro, R., Boutros, M. and Merdes, G.
A combined ex vivo and in vivo RNAi screen of Notch signaling in Drosophila reveals an extensive interaction network.
Developmental Cell 2010 May;18(5):862-876. (PubMed).
Funding
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