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 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, 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 fundamental and enduring mystery 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), a transcription factor that defines the ?wing? state. We have 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 and its transcriptional effector Yorki (Yki, a YAP). 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. We will also seek to clarify how Wg and Dpp move through tissue to achieve the appropriate range, and to determine the mechanism(s) responsible for terminating growth when the wing reaches the correct size. Finally, we will ask if the principles we elucidate in the wing can be generalized to other organ systems in the fly.
Perturbations of the intercellular signaling systems that control tissue growth are a major source of human disease, associated with a wide range of developmental, physiological disorders as well as most forms of cancer. The proposed research is relevant to public health because solving how such systems normally function to direct as well as terminate growth as organs develop 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.
