Genetic Analysis of Epithelial Morphogenesis and Organ Shape

上皮形态发生和器官形状的遗传分析

• 批准号: 7948098
• 负责人: Sally Horne-Badovinac
• 金额: $ 28.58万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7948098
• 关键词: Address; Adhesions; Anterior; Basement membrane; Biochemical; Biological; Cell Polarity; Cell physiology; Cells; Complement; Congenital Abnormality; Development; Drosophila genome; Drosophila genus; Embryonic Development; Employee Strikes; Epithelial; Epithelium; Event; Extracellular Matrix; Eye; Filament; Filopodia; Genetic; Genetic Screening; Genetic Techniques; Goals; Heart; Image Analysis; Imaging Techniques; Individual; Investigation; Kidney; Labyrinth; Life; Mediating; Metabolic Diseases; Microfilaments; Molecular; Morphogenesis; Mutation; Neural tube; Nurses; Oocytes; Organ; Pathway interactions; Pattern; Phosphotransferases; Play; Population; Process; Publishing; Regulation of Cell Shape; Research; Rest; Role; Screening procedure; Shapes; Side; Signal Pathway; Signal Transduction; Surface; System; Testing; Tissues; Wing; Work; anterior chamber; cell behavior; cell type; design; egg; fly; gene function; genetic analysis; genetic manipulation; interest; migration; mutant; novel; polarized cell; public health relevance

DESCRIPTION (provided by applicant): The long term goal of this research is to determine how the dynamic regulation of cell shape, polarity and adhesion across cell populations sculpts an organ's shape during development. To this end, we are using genetic and cell biological approaches in Drosophila to investigate how a novel form of planar polarity within the follicle cell epithelium creates the elongated shape of a simple organ-like unit known as an egg chamber. Planar polarity is a developmental mechanism in which individual cells are coordinately polarized within the plane of a tissue to provide directional information for subsequent morphogenetic events. Pioneering work on this phenomenon in the fly wing and eye led to the discovery of the Frizzled planar cell polarity pathway, which is now known to shape the vertebrate body axis, inner ear, kidneys and neural tube. The Frizzled signaling cassette plays no role in egg chamber elongation, however, indicating that the investigation of this process is likely to define a new and perhaps similarly conserved molecular framework regulating planar polarity and organ shape. Our first two specific aims are designed to elucidate the cellular mechanisms that underlie this unconventional planar polarity system. Aim 1 will use genetic manipulations to test the hypothesis that a specialized cell type known as the polar cells induces planar polarity in the neighboring follicle cells, while Aim 2 will use fixed and live imaging techniques to explore the development and function of a polarized cell protrusive activity that represents the most dramatic morphological readout of planar polarity in this tissue. To complement these cellular analyses, we performed a pilot genetic screen that identified a key molecular pathway regulating planar patterning and morphogenesis in this epithelium. Aim 3 will use genetic and biochemical approaches to investigate the function of this signaling cascade, and Aim 4 will employ a highly efficient screening strategy to extend the search for novel egg shape regulators to other regions of the Drosophila genome. Together these studies will reveal the cellular and molecular mechanisms controlling follicle cell planar polarity and egg chamber elongation, and are likely to reveal general principles guiding organ morphogenesis in wide range of systems. PUBLIC HEALTH RELEVANCE: The proper function of vital organs requires that they attain their proper shapes during embryonic development. When these processes go awry, birth defects metabolic diseases result. The goal of this research is to use the experimental tractability of fruit flies to reveal novel cellular and molecular mechanisms guiding organ morphogenesis.

描述（由申请人提供）：这项研究的长期目标是确定细胞形状，极性和粘附的动态调节如何在发育过程中雕刻一个器官的形状。为此，我们正在使用果蝇中的遗传和细胞生物学方法来研究卵泡细胞上皮中一种新型的平面极性形式如何产生一个简单的器官状单元的细长形状，称为卵室。平面极性是一种发育机制，其中单个细胞在组织平面内占极两极化，以提供方向信息以进行随后的形态发生事件。在飞翼和眼睛中，关于这种现象的开创性工作导致发现了卷曲的平面细胞极性途径，该途径现在已知可以塑造脊椎动物的身体轴，内耳，肾脏和神经管。但是，卷曲的信号盒在卵室的伸长率中没有作用，但表明对该过程的研究可能会定义一个新的，也许是类似保守的分子框架，可调节平面极性和器官形状。我们的前两个特定目标旨在阐明这种非常规平面极性系统的基础的细胞机制。 AIM 1将使用遗传操纵来检验以下假设：被称为极性细胞的专用细胞类型会在相邻的卵泡细胞中诱导平面极性，而AIM 2将使用固定和实时成像技术来探索极化细胞突出活性的发育和功能，这代表了该物体中最具戏剧性的平面读数。为了补充这些细胞分析，我们进行了一个试点遗传筛选，该筛选鉴定了一个关键的分子途径，该途径调节了该上皮中的平面图案和形态发生。 AIM 3将使用遗传和生化方法来研究该信号级联的功能，AIM 4将采用高效的筛选策略，将寻找新型卵形调节剂的搜索扩展到果蝇基因组的其他区域。这些研究共同揭示了控制卵泡细胞平面极性和卵室伸长的细胞和分子机制，并可能揭示了指导器官形态发生的一般原理。 公共卫生相关性：重要器官的适当功能要求它们在胚胎开发过程中达到适当的形状。当这些过程出现问题时，先天缺陷会导致代谢疾病。这项研究的目的是利用果蝇的实验性障碍性来揭示指导器官形态发生的新型细胞和分子机制。