(333h) An in-Silico Synthetic Approach to Elucidate Design Principles Underlying Bi-Directional Gradient Sensing in Eukaryotic Cells

Many cells (both bacteria and eukaryotes) respond to gradients of concentrations of  chemicals in their environment  by exhibiting directional migration, a process known as chemotaxis. This process plays very important biological and physiological roles. In many cases, the movement is up-gradient, and the process is referred to as chemoattraction, and in some other cases, the movement is down-gradient and the process is referred to as chemoorepulsion.  It has been experimentally found that different eukaryotic cells are capable of both chemoattraction and chemorepulsion, either to different chemicals, or in some cases to the same chemical but under different conditions. It is thus important to examine what features in the wiring of the signalling networks and their organization allow the cell to exhibit both these features, and how this affects the signal transduction in each case. In this talk we will use an in-silico synthetic approach to examine different design features in the wiring of signalling networks to give rise to such behaviour, in light of known complexities in signalling in eukarytotic chemotaxis.

We do this by systematically analyzing two cases, motivated by their postulation and discussion in the experimental literature. The first is that of a “polarity switch” and the second is the role of competing signalling effects at the gradient sensing. For each of these cases, we will discuss how these basic network wiring possibilities may allow for the cell to exhibit attractive and repulsive response, and then examine how this works upstream of different qualitative signalling behaviour such as adaptation and spontaneous polarization. This is achieved by “connecting” the relevant modules in-silico.  This systematic approach reveals the behaviour of each design feature, the capabilities and constraints involved. We will then discuss the implication of our various results in the context of the known signalling of different eukaryotic cell types. Overall this synthetic approach provides a design framework and "systems skeleton"for examining and elucidating design principles of attractive/repulsive gradient sensing in multiple systems.