Juxtacrine signaling is inherently noisy.

Juxtacrine signaling is an important class of signaling systems that plays a crucial role in various developmental processes ranging from coordination of differentiation between neighboring cells to guiding axon growth during neurogenesis. Such signaling systems rely on the interaction between receptors on one cell and trans-membrane ligands on the membrane of a neighboring cell. Like other signaling systems, the ability of signal-receiving cells to accurately determine the concentration of ligands, is affected by stochastic diffusion processes. However, it is not clear how restriction of ligand movement to the two-dimensional (2D) cell membrane in juxtacrine signaling affects the accuracy of ligand sensing. In this study, we use a statistical mechanics approach, to show that long integration times, from around one second to several hours, are required to reach high-sensing accuracy (better than 10%). Surprisingly, the accuracy of sensing cannot be significantly improved, neither by increasing the number of receptors above three to five receptors per contact area, nor by increasing the contact area between cells. We show that these results impose stringent constraints on the dynamics of processes relying on juxtacrine signaling systems, such as axon guidance mediated by Ephrins and developmental patterns mediated by the Notch pathway.