The main goal of this grant is to determine how morphogens control organ growth during animal development. Morphogens are secreted signaling molecules that spread through developing tissues and control gene expression, pattern, polarity and growth. The major superfamilies of morphogens are conserved in all multi- cellular 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 neurological 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, were instrumental in establishing that members of three superfamilies of secreted proteins, Wingless/Ints (Wnts), Bone Morphogenetic Proteins (BMPs) and Hedgehogs (Hhs) all function as bona fide morphogens. Initially these studies were focused on determining both the logic and molecular mechanisms by which these molecules control gene expression, pattern and polarity. Here, we turn to the more challenging problem of how they organize growth. In the proposed research, we will test and extend a new model we have posited for growth based on our recent discoveries about how Drosophila Wingless (Wg), a founding member of the Wnt superfamily, controls the dramatic expansion of the developing wing, a classic paradigm for morphogen action. In this model, Wg and a second morphogen Decapentaplegic (Dpp), a BMP, act together to sustain the growth of wing cells and to recruit new cells into the wing primordium by regulating expression of the selector gene, vestigial (vg), and a transcription factor that defines the "wing" state. We have preliminary evidence that the key events in this process are mediated by a single enhancer element in the vg gene, which integrates Wg and Dpp input, as well as a third "recruitment" signal that depends on transient activation of the conserved Warts-Hippo tumor suppressor pathway. We will combine genetic, transgenic and molecular approaches to establish the roles of all three signaling systems, as well as the molecular mechanism(s) by which they are integrated by this enhancer. In addition, we will analyze three limits to morphogen-dependent wing growth, namely the capacity of morphogens to spread, the inhibitory action of JAK/Stat signaling from surrounding tissue, and the reliance on changing levels of the systemic steroid hormone Ecdysone. These experiments will either confirm and advance our model for the control of organ growth- a fundamental, unsolved problem in all animals - or lead to new, testable hypotheses.
Perturbations of the intercellular signaling systems that control tissue growth are a major source of human disease, associated with a wide range of developmental and neurological disorders as well as most forms of cancer. The proposed research is relevant to public health because solving how tissues normally grow to the right size, and then stop growing, is essential for the development of more effective diagnostic and therapeutic treatments for this enormously broad range of afflictions. Thus, the proposed research is relevant to NIH's mission to reduce the burden to society arising from genetic and environmental disorders of fundamental aspects of human development and physiology.