UC Irvine

Although developing organisms of the same species may vary in size, the proportions of body sizes are kept remarkably constant. They do so even in the face of perturbations to growth. Morphogen gradients provide positional information in a concentration-dependent manner, and are linked to organ patterning and the control of organ size. To achieve proportional patterning morphogen gradients need to scale with the size of the tissue. This has been demonstrated for gradients of decapentaplegic (Dpp), a homolog of vertebrate bone morphogenetic proteins (BMPs), which regulates pattern and growth in the wing imaginal disc of the fruit fly Drosophila melanogaster. It has been argued that Pentagone (Pent), a secreted protein whose expression is repressed by Dpp, plays a central role in scaling the wing disc Dpp gradient, because the Dpp activity gradient of Pent mutants is severely contracted and does not scale well. It has been proposed that Pent acts as the expander in an “expansion-repression” feedback circuit that produces automatic gradient scaling. In agreement with this model, I found that Pent controls the spread of Dpp molecules in the wing disc, but in strong disagreement with it, I found that Pent has a very short spatial decay length, i.e. its biological activity does not spread far from its sites of synthesis. I used experiments to examine how Pent regulates Dpp spread, and mathematical modeling to explore how Pent acts locally to scale the Dpp gradient globally. I showed that Pent spreads the Dpp gradient by inhibiting the function of co-receptors at the edge of the wing disc. Based on that, I propose a modified expander-repressor model that can work even if Pent has a short decay length. The model predicts that Dpp-mediated feedback regulation of the receptor Thickveins (Tkv) and the co-receptor Division abnormally delayed (Dally) is necessary for scaling. I present experimental evidence that this is in fact the case.