Pattern formation analysis by colored Petri nets with quantitative manipulation of a gene

We propose a new approach of modeling and simulation for analyzing multicellular biological events by combining colored hybrid Petri nets (CoIHPNs) with newly devised biological experiments that can control the level of a gene quantitatively. We analyzed the patterning of boundary cells in the Drosophila large intestine, where one-cell-wide domain of boundary cells differentiate through Delta-Notch signaling. Biological experiments regulating the level of Delta result in six distinct patterns of boundary cells corresponding with the level of Delta. All these patterns were successfully reproduced by simulation based on ColHPN modeling only by changing the parameter related to the level of Delta. By monitoring the concentration of the active form of Notch in each cell during simulation, it was revealed that these distinct modes of patterning correlate with the fluctuation range of active Notch. Combination of simulation and quantitative manipulation of a gene activity described here is a reliable and powerful approach for analyzing and understanding the patterning process regulated by Notch signaling.