System level analysis of the BMP4 synexpression groups
Final Report Abstract
Synexpression groups are clusters of genes that share a complex expression pattern and function in the same molecular pathway, such as protein secretion, chromatin structure and cell signaling. They are a widespread phenomenon and have been identified from yeast to man. Their identification allows to assemble molecular pathways and to predict unknown protein function. Synexpression groups are autoregulatory modules and we have suggested that negative feedback regulators within groups encompassing growth factor signaling cascades regulate system properties such as robustness, signal spread and decay. In the project we focussed on the BMP signalling pathway which plays a pivotal role throughout development. Notably, a BMP4 morphogen gradient plays a key role in embryonic development, and we are beginning to understand how the self-regulating properties of its signaling circuitry ensure robust embryonic patterning. Many of the BMP4 pathway components are coordinately expressed, forming a synexpression group and act as positive or negative feedback modulators. In this project we had asked a number of specific questions concerning negative feedback in the BMP4 synexpression groups: • What is the role of the feedback regulatory loop in BMP signalling? • What happens to the system properties (signal saturation, dose response, kinetics, variation, signal spread) when feedback regulation is blocked? • What advantage does synexpression network organisation confer to the system (e.g. robustness, fidelity)? We have used three approaches to address these system biology questions: • Real time BMP signaling assays in cultured mammalian cells. • In vivo BMP signaling assays in Xenopus embryos. • Mathematical modelling in collaboration with Dr. Stefan Legewie. Through the combination of these we found that the synexpressed feedback inhibitors BAMBI, SMAD6, and SMAD7 (i) expand the dynamic BMP signaling range essential for proper embryonic patterning and (ii) reduce inter-individual phenotypic and molecular variability in Xenopus embryos. Thereby, negative feedback linearizes signaling responses and confers robust patterning, thus promoting canalized development. The presence of negative feedback inhibitors in other growth factor synexpression groups suggests that these properties may constitute a general principle.
Publications
- (2011). Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development. Proc. Natl. Acad. Sci. USA 108, 10202–10207
Paulsen, M., Legewie, S., Eils, R., Karaulanov, E., Niehrs, C.
