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

管形成是许多器官发育的重要过程，包括肺、肾、肠和心脏，因此在细胞和分子水平上理解这一过程至关重要。该建议的目的是阐明多肌醇多磷酸磷酸酶（Mipp 1）在果蝇气管发育中的作用，这是研究管状器官发生的最佳模型系统之一。Mipps是分解高级肌醇多磷酸（InsP）的主要酶，InsP是许多重要细胞过程的重要第二信使。Mipps的生物学功能知之甚少。mipp 1被鉴定为Trachealess（Trh）的下游靶标，Trachealess是调节气管形成的整个过程的关键转录。mipp 1基因敲除成功产生，其表型特征显示显著的背干延长和神经节分支误移缺陷。这些初步的结果导致的假设，Mipp 1调节参与限制背干长度和指导神经节分支迁移的分子的生产。具体目标1的A部分将通过分析与Mipp 1的缺失和过表达相关的气管表型来定义Mipp 1在气管发育中的作用。具体目标1的B部分将揭示Mipp 1是否通过影响气管背干管尺寸控制和神经节分支迁移的已知途径或通过新途径发挥作用。具体目标2将通过比较mipp 1敲除和mipp 1 mipp 2双无效突变体的气管表型来测试果蝇Mipp 2是否补偿Mipp 1活性。具体目标3将揭示Mipp 1是否通过从InsP 5和InsP 6产生InsP 4、InsP 3或通过从2，3-二磷酸甘油酸产生2-磷酸甘油酸来调节管尺寸控制和分支迁移。将操纵平行途径中编码酶的基因来构建Mipp 1底物或产物，以了解哪些分子与在mipp 1突变体中观察到的气管缺陷相关。Mipp在果蝇胚胎气管的非常易处理的系统中的功能的分析可能提供对这个高度保守的蛋白质家族如何在高等动物中发挥功能的深入了解。

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.