Contact-mediated long distance signaling by Drosophila cytonemes. Sougata Roy, Thomas B Kornberg. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA.

   How cells communicate with each other at long distances is key to understanding how cells cooperate to form organized tissues during development and why cells in various disease states lose or escape normal controls. Although much progress has been made identifying signaling molecules that mediate these communications - proteins such as Hedgehog, Wingless, Decapentaplegic (Dpp, a BMP homolog), Fibroblast Growth Factor and Epidermal Growth Factor - the mechanism by which these proteins move with target specificity and in regulated amount through and across tissues remains unproven. Several proposed models postulate that some form of diffusion moves these signaling proteins through extracellular spaces. My work has investigated a different direct delivery mechanism whereby specialized filopodia (cytonemes) transfer signaling proteins between cells at sites of direct contact (Roy and Kornberg, Sci Signal. 2011; 4:pt8). Cytonemes are types of filopodia first identified in the Drosophila wing imaginal disc that were proposed to be involved in long distance signaling during development. My work shows that same group of cells emanate different types of cytonemes that can be distinguished by their specific response to different signaling ligands depending on the presence or absence of different signaling protein receptors in them (Roy et al. Science. 2011; 332:354-358). I then show, using the GRASP GFP reconstitution method, that cytonemes make direct contact with target cells, and also show that contacting cytonemes exchange, receive and transport morphogen molecules from target cells to recipient cells in receptor dependent manner. Finally, I show that genetic conditions that reduce cytoneme-mediated contacts also reduce signal transduction. These findings establish that non-neuronal cells can make direct long distance contacts for signal transduction and support the model of cytoneme-based movement of signaling proteins as a novel and essential mechanism for cell-cell communication.