Saxophone: A glucose-sensitive type I Dpp/BMP receptor

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Discoveries made in the fruit fly Drosophila melanogaster concerning how signaling pathways are built and how those pathways are controlled by metabolic signals provide a foundation for understanding developmental abnormalities that arise due to both an environmental and genetic component. In particular, recent breakthrough studies linked fruit fly fertility to its nutritive environment. In conditions of low glucose, female fruit flies have 35% fewer progeny, with reduced fertility resulting from a high rate of embryonic lethality. Molecular studies revealed the Saxophone (Sax) receptor to be the metabolite-sensitive point of a signaling pathway that is essential for proper embryonic development (in this case the Bone Morphogenetic Protein or BMP signaling pathway). The current study will employ genetic (mutant analysis), molecular (sequence analysis), and biochemical (mass spectrometry) methods to probe: 1) the mechanism of metabolite-mediated regulation of Sax, and 2) the pathway’s evolutionary history. This multipronged and multidisciplinary study will also provide an integrative platform for educating students from middle school to graduate school in modern research methods. Inclusion of students from Salt Lake Center for Science Education (SLCSE), a magnet school in Salt Lake City serving a high proportion of economically disadvantaged (40%) and minority (48%) students in grades 8-12, in the research program is expected to contribute to improved science self-efficacy and facilitate retention of underserved student populations in science, technology, engineering, and mathematics (STEM). Activation and inhibition of BMP (Bone Morphogenetic Protein) signaling pathways at the right time and place is essential for all animal life, with defects in signaling leading to devastating abnormalities. Importantly, the breakthrough finding in Drosophila that O-linked-N-acetylglucosaminylation (O-GlcNAcylation) regulates Dpp (Decapentaplegic, a Drosophila BMP) signal transduction reveals new avenues for studies of the relationship of the environment to emergent developmental and physiological systems. In this project, the relationship of O-GlcNAcylation to Dpp signaling during development is assessed in the genetically tractable fruit fly model. Tests of the hypothesis that O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates a nutrient-sensitive branch of the BMP/Dpp signaling family are central to the proposed research, and three lines of investigation are undertaken. First is a determination of how O-GlcNAc modifies the type 1 Dpp receptor Saxophone (Sax). Second is a determination of how bioactivities of the Thickveins (Tkv) and Sax type 1 receptors differ. Last is a determination of whether the nutrient-sensitive Sax arm of the Drosophila Dpp receptor pathway is conserved. The research proposed here will be used to introduce students from middle school to graduate levels to model systems genetic research. Establishment of long-term mentor-student relationships, especially with students from SLCSE (Salt Lake Center for Science Education), a magnet school in Salt Lake City serving a high proportion of economically disadvantaged (40%) and minority (48%) students in grades 8-12, is expected to improve science citizenship, trust, and scholarship, and facilitate student success in attaining independent STEM cell careers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.