Stochasticity in Cell-Cell Contact Length Skews Juxtacrine Signal Output

Juxtacrine signaling is an important means of intercellular communication which depends on direct contact between a signal sending and signal receiving cell. Time-variance in the cell-cell contact area can alter the signal output, and is an important mechanism to understand. Here we consider synNotch, which modifies the natural juxtacrine signaling pathway, Notch, to express Green Fluorescent Protein (GFP) and allow for the measurement of signaling response. We previously identified the importance of cell-cell contact length on synNotch output, and observed large variations in contact lengths in vivo. Contact lengths could also vary with time, and the direct impact of this variation on signal output is what we investigate here through stochastic simulations based on the Gillespie Algorithm. We observe a predictable shift in the equilibrium signal output due to time-variant contact lengths. We identify the importance of variability in cell-cell contact geometry and its timescale relative to synthesis and decay of biological signals and the shift that this can cause in average signal outputs. The implications of our findings highlight that the timescale of contact fluctuations can modulate signaling strength and patterning outcomes.