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

在果蝇黑腹果蝇（Drosophila melanogaster）中关于信号通路如何构建以及这些通路如何受代谢信号控制的发现，为理解由环境和遗传因素引起的发育异常提供了基础。特别是，最近的突破性研究将果蝇的繁殖能力与其营养环境联系起来。在低葡萄糖条件下，雌性果蝇的后代减少35%，胚胎死亡率高导致生育力下降。分子研究表明，萨克斯管（Sax）受体是一个信号通路的代谢物敏感点，该信号通路对胚胎正常发育至关重要（在这种情况下是骨形态发生蛋白或BMP信号通路）。目前的研究将采用遗传（突变分析）、分子（序列分析）和生化（质谱）方法来探索：1)代谢物介导的Sax调控机制，2)该途径的进化史。这项多管齐下、多学科的研究也将为从中学到研究生学习现代研究方法提供一个综合平台。盐湖城科学教育中心（SLCSE）是盐湖城的一所磁极学校，为8-12年级的高比例经济弱势群体（40%）和少数民族（48%）学生提供服务。纳入该研究项目的学生预计将有助于提高科学自我效能，并促进保留科学、技术、工程和数学（STEM）领域服务不足的学生群体。在适当的时间和地点激活和抑制BMP（骨形态发生蛋白）信号通路对所有动物的生命都是至关重要的，信号通路的缺陷会导致毁灭性的异常。重要的是，在果蝇中，o -链接- n -乙酰氨基葡萄糖化（o - glcnac酰化）调节Dpp （Decapentaplegic，一种果蝇BMP）信号转导的突破性发现为研究环境与新兴发育和生理系统的关系开辟了新的途径。在本项目中，在遗传可处理的果蝇模型中评估了发育过程中o - glcn酰化与Dpp信号传导的关系。O-linked β - n -乙酰氨基葡萄糖（O-GlcNAc）调节BMP/Dpp信号家族的营养敏感分支的假设测试是拟议研究的核心，并进行了三条调查。首先是确定O-GlcNAc如何修饰1型Dpp受体萨克斯（Sax）。其次是确定厚静脉（Tkv）和Sax 1型受体的生物活性如何不同。最后是确定果蝇Dpp受体通路的营养敏感的Sax臂是否保守。这里提出的研究将用于介绍学生从中学到研究生水平的模型系统遗传研究。建立长期的师徒关系，特别是与SLCSE（盐湖城科学教育中心）的学生建立长期的师徒关系，SLCSE是盐湖城的一所磁铁学校，为8-12年级的高比例经济弱势（40%）和少数民族（48%）学生提供服务，有望提高科学公民身份，信任和奖学金，并促进学生在独立的STEM事业中取得成功。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.