Dynamical basis of cellular sensing and responsiveness to spatial-temporal signals

Abstract

Under physiological conditions, cells continuously sense and migrate in response to chemoattractant signals that are noisy, conflicting, and changing over time and space. This suggests cells exhibit seemingly opposed characteristics, such as robust maintenance of polarized state longer than the signal duration, while still remaining adaptive to novel signals. However, the dynamical mechanism that enables such sensing capabilities is still unclear. In this thesis, I propose a generic dynamical mechanism based on critical positioning of receptor signaling network in the vicinity of saddle-node of a sub-critical pitchfork bifurcation (SubPB mechanism). The critical organization leads to the emergence of a dynamical "ghost" that gives transient memory in the polarized response, as well as the ability to continuously adapt to changes in signal localization. Using weakly nonlinear analysis, an analytical description of the necessary conditions for the existence of this mechanism in a general receptor network is provided. Comparing to three classes of existing mathematical models for polarization that operate on the principle of stable attractors, I demonstrate that the metastability arising from "ghost" in the SubPB mechanism uniquely enables sensing dynamic spatial-temporal signals in a history-dependent manner. By using a physical model that couples signaling to morphology, I demonstrate how this mechanism enables cells to navigate in changing environments. Using the well characterized Epidermal growth factor receptor (EGFR) sensing network in epithelial cells, I demonstrated that the described transient memory in signaling mimics working memory in neurons, enabling cells to process non-stationary signals.