PROJECT SUMMARY The main goal of this project is to determine how morphogens control organ growth. During development, each body part grows to full size and differentiates complex cell patterns under the control of morphogens, secreted signaling molecules that spread through developing tissues and organize gene expression, pattern and growth. The major superfamilies of morphogens are conserved in all multicellular animals, from sponges to man. Understanding how they work has enormous implications for human health, as genetic and environmental perturbations of their activities and signal transduction pathways cause diverse developmental and physiological disorders as well as a wide range of cancers. Research on morphogens is thus critical for developing diagnostic and therapeutic tools to treat human disease, a central mission of the NIH. Our past studies, using Drosophila, established that members of two superfamilies of secreted proteins, Bone Morphogenetic Proteins (BMPs) and Wingless/Ints (Wnts) function as bona fide morphogens. Initially we focused on the logic and molecular mechanisms by which these molecules control gene expression and patterning. Here we turn to the fundamental and enduring mystery of how they control growth. In the proposed research, we will fill three key gaps in understanding. First, we will consolidate and extend a new “feed-forward” model for growth based on our recent discoveries unifying the roles of Decapentaplegic (Dpp, a BMP) and Wingless (Wg) in the developing Drosophila wing, a classic paradigm for morphogen action. In this model, Wg and Dpp act together to induce and sustain expression of the selector gene, vestigial (vg), which encodes a transcription factor that “selects” the wing state and programs wing cells to grow in response to Wg and Dpp. We identified a single enhancer element in the vg gene that integrates Dpp and Wg input, as well as a “recruitment” signal, the protocadherin Fat. We will now combine genetic, transgenic and molecular approaches to determine how this integration occurs and to identify downstream effectors that govern wing growth in response to Dpp and Wg. We will also test a key axiom of the model—that Dpp and Wg are required continuously, at long-range, to sustain growth—and determine how these molecules move through tissue. Second, we will apply the approaches and principles that have emerged from our analysis of the fly wing to elucidate how Dpp and Wg control the growth of other organs. We will focus on the fly leg in which Dpp and Wg as well as their downstream selector genes and signaling molecules are deployed in a manner that is highly conserved throughout the animal kingdom, but distinct from the wing. Our analysis will build on our preliminary evidence that leg growth is governed by the ranges of Dpp and Wg—as in the wing—but by different regulatory circuits and logic. Third, we will determine the role of receptor dimerization or higher order oligomerization in Wg reception ...