The high degree of conservation of fundamental biological processes across all animals, coupled with the broad repertoire of fly genetic approaches makes the fruit fly Drosophila melanogaster a uniquely powerful system for understanding a broad range of developmental processes. In this study, genetic methods are employed to identify, clone, and characterize genes required for fruit fly dorsal closure. Dorsal closure is the developmental process by which a cell sheet completely encases a developing fruit fly embryo. The dorsal closure process is analogous to tube formation, with the edges of the epithelial sheet meeting and fusing at the dorsal midline. Virtually all of the molecules essential for the changes in cell shape and position that drive dorsal closure are conserved, and they are required for a variety closure processes in all vertebrates. These conserved processes include eyelid and neural tube fusion, as well as wound healing. One's ability to dissect and characterize dorsal closure in the experimentally tractable fruit fly, therefore, provides a powerful system to elucidate a fundamental development process. The foci of the studies described here are two Drosophila proteins that were recently identified as being critical for dorsal closure: Raw (a novel protein) and Mummy (a UDP]Nacetylglucosamine pyrophosphorylase). Given the conservation of these developmental pathways, these proteins are likely important for neural tube closure as well as for dorsal closure. Thus, the definition of the roles that Raw and Mummy play in the developing fruit fly facilitates identification of the molecular events necessary for key developmental events. This project will provide undergraduates and high school students from the community with 'hands-on' research training opportunities. In the past this research has been highlighted at the University of Utah's Museum of Natural History, as well as additional community venues. Teaching and community outreach remains a high priority for the future.
Critical to the development of all multicellular organisms is the ability to transform equipotent embryonic cells into distinct differentiated tissues and organs. One way this cellular diversity is created is via morphogen signaling. Morphogens were first defined by Alan Turing in his 1952 landmark paper as diffusible chemicals that form signaling gradients and by which different chemical concentrations determine different cellular reactions. In 1969, Lewis Wolpert refined our understanding of morphogen gradients with the French Flag model. In this revised model, a diffusible ligand forms a gradient across a signaling field (or between a source and distant cells), and cells within the signaling field act in accordance with the level of signal observed. Among others researching cellular signaling, including Francis Crick, it was quickly noted that generation of a stable continuous gradient requires a "sink", a signal-destroying component located at a distance from the source. Without a sink, signal is expected to accumulate at uniform levels across the field. While mathematical models and molecular visualizations of gradients provide irrefutable evidence for sinks, until now the genetic and molecular nature of a signaling sink working locally or at a distance had not been identified. In our most significant studies from the last six months of our NSF-supported genetic studies of signaling in the Drosophila embryonic epidermis, we showed that UDP-Glucose is required to modulate Dpp gradient formation (Humphreys et al., 2013) and that in flies, chondroitin sulfate, a proteoglycan formed from UDP-glucose, functions as the Dpp sink in the embryonic epidermis and mesoderm (Humphreys et al., in prep). Our results are particularly exciting as they provide a capstone piece to a long-held seminal developmental theory. In additional cell signaling studies, we have shown that phosphorylation is not required for Jun activity when Jun levels are high, and that the embryonic epidermis is marked by several Jun signaling centers that are essential for proper development of differentiated organ systems underlying the epidermis. Each of these findings will serve as the foundational piece for a primary research paper whose lead author will be my graduate student Molly Jud. (Molly is credited with shared first authorship of the 2013 Developmental Biology paper cited above). With respect to broader impacts, Molly has been particularly instrumental in helping me to train female undergraduates (including one URM) as future independent research scientists. Mentoring young women in all aspects of science remains a very high priority for me.
