Visualizing cell proximity with genetically encoded bioluminescent reporters.

Cell-cell interactions underlie diverse physiological processes ranging from immune function to cell migration. Dysregulated cellular crosstalk also potentiates numerous pathologies, including infections and metastases. Despite their ubiquity in organismal biology, cell-cell interactions are difficult to examine in tissues and whole animals without invasive procedures. Here, we report a strategy to noninvasively image cell proximity using engineered bioluminescent probes. These tools comprise "split" fragments of Gaussia luciferase (Gluc) fused to the leucine zipper domains of Fos and Jun. When cells secreting the fragments draw near one another, Fos and Jun drive the assembly of functional, light-emitting Gluc. Photon production thus provides a readout on the distance between two cell types. We used the split fragments to visualize cell-cell interactions over time in vitro and in macroscopic models of cell migration. Further application of these tools in live organisms will refine our understanding of cell contacts relevant to basic biology and disease.