Formation of the Drosophila salivary gland

果蝇唾液腺的形成

• 批准号: 10660311
• 负责人: Deborah J Andrew
• 金额: $ 63.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660311
• 关键词: 3-Dimensional; Acute; Address; Affect; Apical; Architecture; Binding; Binding Sites; Biological Models; Cell Death; Cell Shape; Cells; Cessation of life; Chromatin; Consensus; DNA Binding; Development; Drosophila genus; Embryo; Enhancers; Epithelium; Event; Family; Family member; Gene Expression; Genes; Genetic; Head; Hindgut; Histones; Homeostasis; Human; Human Development; Integral Membrane Protein; Kidney; Learning; Lipids; Liver; Lung; Maintenance; Malignant Neoplasms; Mammals; Maps; Mechanics; Mediating; Metabolic Diseases; Modeling; Molecular; Morphogenesis; Morphology; Motor; Mutation; Myosin Type II; Nucleic Acids; Occupations; Organ; Organ Size; Pancreas; Participant; Physiological; Physiology; Play; Positioning Attribute; Primitive foregut structure; Proteins; Regulation; Regulatory Pathway; Repression; Role; Salivary Glands; Shapes; Site; Specific qualifier value; Testing; Time; Tissues; Tube; Winged Helix; Work; fitness; genetic regulatory protein; gland development; hepatic necrosis; liver-specific protein; migration; mutant; non-muscle myosin; organ growth; outer surface lipoprotein; prevent; protein function; recruit; sugar; tool; transcription factor; two-dimensional; vertebrate embryos; zygote

The FoxA family of winged-helix DNA-binding transcription factors (TFs) play major roles in the development of many organs in vertebrate embryos. In some cases, they are proposed to be determinants of specific cell fates because they are expressed early and continuously in forming organs, and they are capable of what has been referred to as “pioneer” function – the ability to bind their target motifs even in closed chromatin, whereupon they can “open” that chromatin to make it accessible to other key tissue-specific “settler” TFs. Combined, the pioneer and settler TFs activate expression of the genes controlling tissue morphogenesis, specialization and homeostasis through their sequence-specific interactions with the corresponding target gene enhancers. As with the vertebrate FoxA TFs, the single FoxA orthologue in Drosophila, known as Fork head (Fkh), plays major roles in the formation of multiple organs and in controlling the survival, morphology and physiology of the salivary glands (SG). The relative simplicity of the Drosophila embryonic SG, the non-redundancy in Fkh function, the short development time, ex utero development, and the huge armamentarium of excellent genetic tools make this an ideal model system for testing current models for vertebrate FoxA protein function, for uncovering the mechanisms by which FoxA proteins coordinate morphogenesis with tissue-specific physiological specialization, and for finding and characterizing the downstream effectors that directly impact overall organ architecture and organ placement. In Aim 1, we propose to learn how Fkh works with two other early-expressed SG TFs – Sage and Senseless (Sens) – to regulate expression of the salivary gland “secretome”. Based on earlier findings, these studies will challenge the notion that Fkh has the same pioneering function that has been proposed for the vertebrate FoxA TFs. In Aim 2, we propose to discover and characterize the partner SG TFs and downstream effectors that mediate the FoxA-driven morphological events that transform the two-dimensional salivary gland primordia into three dimensional internalized epithelial secretory organs. These studies will be among the first to reveal how FoxA proteins partner up to drive the morphological changes that underlie tissue development. In Aim 3, we characterize three Fkh morphogenetic targets that help coordinate the abundance, localization and activities of two major players in tissue remodeling – non- muscle Myosin II and the sub-apical transmembrane protein Crumbs. As new targets are discovered (through the earlier aims), we will also determine where, when and how newly discovered morphogenetic players contribute to overall tissue architecture.

翼螺旋DNA结合转录因子（TF）的FoxA家族在转录调控中起主要作用。 脊椎动物胚胎中许多器官的发育。在某些情况下，它们被提议为 特定细胞命运的决定因素，因为它们在形成过程中的早期和持续表达， 器官，它们能够发挥所谓的“先锋”功能- 甚至在封闭的染色质中也能结合它们的靶基序，因此它们可以“打开”染色质， 使其可被其他关键的组织特异性“定居者”TF访问。结合起来，开拓者和定居者 TF激活控制组织形态发生、特化和分化的基因的表达。 通过它们与相应靶基因的序列特异性相互作用的稳态 增强剂。与脊椎动物FoxA TF一样，果蝇中的单一FoxA直系同源物，已知 作为叉头（Fkh），在多个器官的形成和控制 唾液腺（SG）的存活、形态和生理。的相对简单性 果蝇胚胎SG，Fkh功能的非冗余性，发育时间短， 子宫内发育，以及巨大的优良遗传工具的医疗设备使其成为理想的 用于测试脊椎动物FoxA蛋白功能的当前模型的模型系统， FoxA蛋白协调形态发生与组织特异性 生理专业化，并用于寻找和表征下游效应物， 直接影响整个器官结构和器官放置。 在目标1中，我们建议了解Fkh如何与其他两个早期表达的SG TF- Sage一起工作 和无意义（Sens）-调节唾液腺“分泌组”的表达。基于 早期的发现，这些研究将挑战的概念，Fkh具有相同的开创性 功能，已提出的脊椎动物FoxA TF。在目标2中，我们建议发现 并表征了介导FoxA驱动的 将二维唾液腺原基转化为三维唾液腺原基的形态学事件 三维内化的上皮分泌器官。这些研究将是第一批 揭示了FoxA蛋白如何合作，以推动组织的形态变化， 发展在目标3中，我们描述了三个Fkh形态发生靶点， 组织重塑中的两个主要参与者-非- 肌球蛋白II和亚顶端跨膜蛋白Crumbs。新的目标是 发现（通过早期的目标），我们也将确定在哪里，何时以及如何新的 已发现的形态发生参与者有助于整体组织结构。