Synthetic circuits for boundary maintenence

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PJ Steiner, Jim Haseloff

University of Cambridge (Haseloff Lab), United Kingdom

A key feature of development is the spatially organized differentiation of cells that underlies morphogenesis. This self-organization is responsible for many of the extraordinary capabilities of natural biological systems and is so far absent from engineered biological systems. Once initially established, boundaries between cellular populations must be maintained in spite of forces that might otherwise disrupt them. Biological systems employ multiple strategies to this end, including physical mechanisms like differential adhesion and genetic mechanisms like those driven by chemical communication. We have recently shown that clonal sectors of bacterial populations form fractal boundaries through a purely physical emergence process (see poster abstract submitted by Tim Rudge to SB6.0). This suggests that construction of synthetic multicellular systems will require not only mechanisms to establish cohorts of cells, but also mechanisms to maintain the separation of those cohorts. I describe here the ongoing development of a system to maintain an orderly boundary between cellular populations which would otherwise form a fractal boundary due to growth. The genetic circuit employs multiple cross-inhibitory signals and bistability to allow dynamic alteration of cell fate for those cells that cross the boundary between populations. Biophysical and genetic modeling using our software CellModeller demonstrates the feasibility and properties of the system. The in vivo genetic circuit in Bacillus subtilis makes novel use of multiple cross-inhibitory types of the agr system of Staphylococcus aureus for intercellular communication.