The Imperatives of Context and Contour for Morphogen Dispersion

Abstract

The arsenal of signals that cells use to communicate with each other is large and diverse. Some signaling molecules (e.g., nitrous oxide) are small. At the other extreme are proteins such as Drosophila Decapentaplegic (Dpp, a bone morphogenic protein (BMP) homolog), Hedgehog (Hh), Branchless/Fibroblast growth factor (FGF), and Wingless (Wg, a Wnt homolog). In various contexts in many animals, these signaling proteins signal at both short and long distances after moving from producing to recipient cells. Although we are undoubtedly ignorant of many fascinating details about the processes that generate these signals in producing cells and respond to them in recipient cells, the general outlines of production and response are firmly established and many key components have been identified. In contrast, despite much experimental and theoretical work, the question of how these proteins move between cells is controversial. This question is important for elucidating the mechanisms of pattern formation, and its resolution will have broad general implications for cell-cell signaling in many contexts during development and in disease. This essay focuses on the mechanism that distributes the Dpp morphogen across the Drosophila wing imaginal disc. Although many models have been proposed for the formation of the Dpp gradients in the wing disc, a full discussion of their particulars is beyond the scope of this essay. Instead, I focus on the proposal that Dpp diffuses freely in the extracellular space that adjoins the wing disc, and discuss why, despite its claims, a recent study titled “Free Extracellular Diffusion Creates the Dpp Morphogen Gradient of the Drosophila Wing Disc” from Zhou et al. (1) does not settle the issue. The free extracellular diffusion model posits that Dpp is released from Dpp-expressing cells, and that Dpp takes a random walk in extracellular space, eventually binding to receptors that are exposed on the outside of target cells. To study how the Dpp gradients form, Zhou et al. (1) applied sensitive visual methods to monitor the movement of an ectopically expressed fluorescent Dpp fusion protein, DppDendra2. Using classical diffusion theory and assumptions about the rates of receptor binding, the size and form of Dpp, and the nature of the extracellular environment, they report that calculations for diffusion rates of free protein conform to their experimental observations of Dpp movement. Of course, correlation is not proof of mechanism; moreover, there are several reasons for concluding that free extracellular diffusion cannot generate the distributions of signaling proteins that must exist in the wing disc. In the discussion that follows, I briefly describe several issues that should discount free extracellular diffusion as a possible mechanism, and also describe an alternative mechanism that I favor: cytoneme-mediated direct delivery.