Function of Mipp1 in Regulating Drosophila Trachea Tube Size and Branch Migration

Mipp1在调节果蝇气管管大小和分支迁移中的作用

• 批准号: 8255332
• 负责人: Yim Ling Cheng
• 金额: $ 4.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255332
• 关键词: Affect; Alleles; Animals; Biological; Biological Models; Biological Process; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cell physiology; Cytosol; Defect; Development; Dorsal; Drosophila Proteins; Drosophila genus; Embryo; Enzymes; Family; Generations; Genes; Genetic; Genetic Transcription; Goals; Heart; Helix-Turn-Helix Motifs; Human Genome; In Situ; Inositol; Inositol Phosphate Metabolism Pathway; Inositol Phosphates; InsP5; Intestines; Kidney; Knock-out; Knockout Mice; Lead; Learning; Length; Lung; Medial; Messenger RNA; Modeling; Molecular; Mus; Mutate; Organ; Organogenesis; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phylogeny; Play; Polycystic Kidney Diseases; Polyphosphates; Postdoctoral Fellow; Process; Production; Proteins; Reaction; Regulation; Reporting; Role; Second Messenger Systems; Staging; System; Tertiary Protein Structure; Testing; Tissues; Trachea; Transcript; Transgenic Organisms; Tube; Tubular formation; Tumor Angiogenesis; base; human disease; insight; interest; loss of function; migration; mouse genome; mutant; novel; overexpression; protein function; second messenger; tool; transcription factor; tumor

Tube formation is an important process in the development of many organs, including the lung, kidney, intestine, and heart, so it is critical to understand this process at both the cellular and molecular level. The goal of this proposal is to elucidate the role of multiple inositol polyphosphate phosphatase (Mipp1) in Drosophila trachea development, which is one of the best model systems for studying tubular organogenesis. Mipps are the main enzymes to dissipate the high order inositol polyphosphates (InsP), which are important second messengers for many important cellular processes. The biological function of Mipps is very poorly understood. mipp1 was identified as a downstream target of Trachealess (Trh), a critical transcription regulating the entire process of trachea formation. A knockout of mipp1 was successfully generated and its phenotypic characterization revealed significant dorsal trunk elongation and ganglionic branch mismigration defects. These preliminary results lead to the hypothesis that Mipp1 regulates the production of molecules involved in limiting dorsal trunk length and directing ganglionic branch migration. Part A of specific aim 1 will define the role of Mipp1 in tracheal development by analyzing the tracheal phenotypes associated with the loss and overexpression of Mipp1. Part B of specific aim 1 will reveal whether Mipp1 functions through the known pathways that affect tracheal dorsal trunk tube size control and ganglionic branch migration or through a novel pathway(s). Specific aim 2 will test if Drosophila Mipp2 compensates for Mipp1 activity by comparing the tracheal phenotypes of mipp1 knockout and mipp1 mipp2 double null mutants. Specific aim 3 will reveal whether Mipp1 functions through the generation of InsP4, InsP3 from InsP5 and InsP6 or through the generation of 2- phosphogylcerate from 2, 3-biphosphoglycerate to regulate tube size control and branch migration. The genes encoding enzymes in parallel pathways will be manipulated to build up Mipp1 substrates or products to learn which molecules are relevant to the tracheal defects observed in mipp1mutants. The analysis of Mipp function in the very tractable system of the Drosophila embryonic trachea is likely to provide insight into how this highly conserved family of proteins functions in higher animals.

管的形成是许多器官发育的重要过程，包括肺、肾、肠和心脏，因此从细胞和分子水平上理解这一过程是至关重要的。多肌醇多磷酸磷酸酶（Mipp1）在果蝇气管发育中的作用是研究管状器官发生的最佳模型系统之一。Mipps是分解高阶肌醇多磷酸（InsP）的主要酶，InsP是许多重要细胞过程的重要第二信使。对Mipps的生物学功能了解甚少。mipp1被确定为无气管（Trh）的下游靶点，Trh是调节气管形成整个过程的关键转录。成功敲除了mipp1基因，其表型特征显示了显著的背干伸长和神经节分支误移缺陷。这些初步结果导致假设Mipp1调节参与限制背干长度和指导神经节分支迁移的分子的产生。具体目标1的A部分将通过分析与Mipp1缺失和过表达相关的气管表型来定义Mipp1在气管发育中的作用。特异性目的1的B部分将揭示Mipp1是通过影响气管背干管大小控制和神经节分支迁移的已知途径起作用，还是通过一种新的途径起作用。特异性目标2将通过比较Mipp1敲除和Mipp1 Mipp2双零突变体的气管表型来测试果蝇Mipp2是否补偿Mipp1的活性。具体目的3将揭示Mipp1是通过从InsP5和InsP6中生成InsP4、InsP3，还是通过从2,3 -双磷酸甘油酸中生成2-磷酸甘油酸来调节管大小控制和分支迁移。在平行途径中编码酶的基因将被操纵来构建Mipp1底物或产物，以了解哪些分子与Mipp1突变体中观察到的气管缺陷有关。对Mipp在果蝇胚胎气管这个非常容易处理的系统中的功能的分析，可能会为了解这种高度保守的蛋白质家族在高等动物中的功能提供见解。