Early Detection of Sudden Transitions in Notch signaling

Abstract Identifying sudden transitions during phenotypic decision-making of complex biological systems can be crucial for our ability to control a cellular state. Yet, prior determination of these sudden transitions or tipping points remains challenging, as biological systems often exhibit only subtle early changes, which are often masked by inherent noise or rapid transition dynamics. Using Notch signaling as a model, we systematically analyze dynamical transitions in Notch-Delta (ND), Notch-Delta-Jagged (NDJ), and Fringe-mediated NDJ systems for both one and two-cell contexts. In the one-cell ND system, critical slowing down (CSD)-based early warning signals (EWSs) reliably capture transitions between sender ( S ) and receiver ( R ) states and remain robust to variation in forcing rate. We further find that flickering is a precursor to transitions in one-cell NDJ system. In contrast, flickering does not occur in the two-cell Notch model due to the presence of a supercritical bifurcation. Our analysis also offers insight into how NICD (Notch Intracellular Domain)-driven and Fringe-mediated asymmetries, along with the strength of external signals, control the emergence of flickering. Overall, this study identifies sudden transitions in Notch signaling under demographic noise and can be extended to other noisy biological systems, with potential applications in drug development and targeted therapeutic interventions.