Essential cellular functions rely on complex networks that coordinate highly dynamic and integrated processes. Paradoxically, our detailed knowledge of their molecular mechanisms has made it difficult to fully appreciate the core concepts involved. Therefore, the fundamental design and dynamic principles of central cellular circuits and the mechanisms that exist to buffer molecular variability and promote phenotypic homogeneity remain poorly explored. We will use the fission yeast cell cycle control as a model essential eukaryotic network to address these challenging questions. Using a synthetic strategy, we recently started exploring the minimal architecture of the mitotic cycle and demonstrated the surprising capacity of fission yeast cells to adopt simpler rewired cell cycle engines. We propose to build on these findings and address two fundamental issues. First, we will generate a series of tunable synthetic cell cycle circuits, based on our original minimal module, that further simplify cell cycle control. These rewired strains will be used to assess the design principles and dynamic components that allow for an effective and robust progression through the major cell cycle transitions. Second, we will investigate how molecular variability inherent to cellular networks can be buffered to promote population homogeneity and our minimal cell cycle systems will allow us to concentrate on the core mechanisms involved. Our studies combining synthetic approaches, genetics, single-cell manipulation in microfluidic chambers and mathematical modeling will provide novel insights into essential aspects of this central process, revealing more general concepts underlying the design of complex eukaryotic networks.
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