Quantitative Analysis of Delta-like 1 Membrane Dynamics Elucidates the Role of Contact Geometry on Notch Signaling

Notch signaling is ubiquitously used to coordinate differentiation between adjacent cells across metazoans. Whereas Notch pathway components have been studied extensively, the effect of membrane distribution and dynamics of Notch receptors and ligands remains poorly understood. It is also unclear how cellular morphology affects these distributions and, ultimately, the signaling between cells. Here, we combine live-cell imaging and mathematical modeling to address these questions. We use a FRAP-TIRF assay to measure the diffusion and endocytosis rates of Delta-like 1 (Dll1) in mammalian cells. We find large cell-to-cell variability in the diffusion coefficients of Dll1 measured in single cells within the same population. Using a simple reaction-diffusion model, we show how membrane dynamics and cell morphology affect cell-cell signaling. We find that differences in the diffusion coefficients, as observed experimentally, can dramatically affect signaling between cells. Together, these results elucidate how membrane dynamics and cellular geometry can affect cell-cell signaling. Khait et al. show large cell-to-cell variability in the diffusion coefficients of the Notch ligand Delta-like 1. A combination of quantitative FRAP-TIRF imaging and mathematical modeling is used to examine the implications of this result on Notch signaling and its dependence on cell-cell contact geometry.