Free Extracellular Diffusion Creates the Dpp Morphogen Gradient of the Drosophila Wing Disc

How morphogen gradients form has long been a subject of controversy. The strongest support for the view that morphogens do not simply spread by free diffusion has come from a variety of studies of the Decapentaplegic (Dpp) gradient of the Drosophila larval wing disc. In the present study, we initially show how the failure, in such studies, to consider the coupling of transport to receptor-mediated uptake and degradation has led to estimates of transport rates that are orders of magnitude too low, lending unwarranted support to a variety of hypothetical mechanisms, such as “planar transcytosis” and “restricted extracellular diffusion.” Using several independent dynamic methods, we obtain data that are inconsistent with such models and show directly that Dpp transport occurs by simple, rapid diffusion in the extracellular space. We discuss the implications of these findings for other morphogen systems in which complex transport mechanisms have been proposed. We believe that these findings resolve a major, longstanding question about morphogen gradient formation and provide a solid framework for interpreting experimental observations of morphogen gradient dynamics. ► We describe how FRAP may fail to provide information about morphogen transport ► We show that most Dpp in the fruit fly wing disc is not undergoing transport ► We visualize and quantify free, extracellular diffusion of a small pool of Dpp ► We explain how transport of such a pool accounts for morphogen gradient formation