Mechanisms of C. elegans Gastrulation

线虫原肠胚形成的机制

• 批准号: 7847680
• 负责人: ROBERT P GOLDSTEIN
• 金额: $ 27.38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847680
• 关键词: Actomyosin; Adhesions; Animals; Apical; Behavior; Biological Assay; Cadherins; Caenorhabditis elegans; Candidate Disease Gene; Cells; Complex; Cytoskeleton; Defect; Development; Developmental Delay Disorders; Disease; Dissection; Drosophila genus; Enhancers; Eye diseases; Funding; Future; Genes; Genetic; Goals; Grant; Homologous Gene; Human; Lateral; Lead; Life; Link; Malignant Neoplasms; Modeling; Molecular; Morphogenesis; Neural Tube Closure; Neural Tube Defects; Neural tube; Organ; Organism; Pattern; Phenotype; Play; Positioning Attribute; Process; Proteins; RNA Interference; Research; Role; Shapes; Side; Signal Transduction; Signaling Molecule; Skin; Study models; System; Tertiary Protein Structure; Testing; Tissues; Work; Xenopus; Zebrafish; base; cell motility; chromosome 3p deletion syndrome; congenital heart disorder; contactin; expectation; gastrulation; gene function; human disease; imaging modality; improved; insight; interest; loss of function; microphthalmia-dermal aplasia-sclerocornea syndrome; novel; precursor cell; protein function; rho; rho GTPase-activating protein

DESCRIPTION (provided by applicant): Morphogenetic processes such as gastrulation, neurulation, and the shaping of organs play critical roles in animal development. We have worked to develop C. elegans gastrulation as a new model for studying mechanisms of morphogenesis. The goal of our research is to use this model to understand some of the mechanisms that can position cells during morphogenesis. We pursue these mechanisms by combining cell manipulations, as has been successful in systems like Xenopus and chick, with genetics, as has been successful in C. elegans, Drosophila and zebrafish. Our expectation is that the ability to combine genetics and cell manipulations in a single system, together with modern live imaging methods, to study a simple model of morphogenesis, will enable us to make some unique and important contributions to understanding mechanisms of morphogenesis. C. elegans gastrulation begins with the internalization of two endodermal precursor cells. Our preliminary studies have implicated contraction of an apical actomyosin meshwork in these cells in their internalization. Our studies have also provided a set of assays that can facilitate thorough dissection of function for new genes. We will (1) determine how a set of adhesion proteins regulates cell movements in gastrulation, (2) determine how adhesion proteins and intracellular signaling molecules contribute together to gastrulation, and (3) based on our results identifying new genes to date, screen for and pursue additional genes that function in the processes studied above. We expect that this model can inform how the cellular and molecular mechanisms of morphogenesis may be disrupted in certain human diseases, most notably in neural tube defects, as neural tube formation and C. elegans gastrulation share certain cellular and molecular mechanisms. Project narrative: We have worked to develop C. elegans gastrulation as a new model for studying mechanisms of morphogenesis, combining genetics, modern live imaging methods, and direct manipulations of cells. The overall goal of our research is to understand the mechanisms that position cells in C. elegans gastrulation, to further understand mechanisms of morphogenesis common to all animals including humans. We expect that this simple model can inform our understanding of cellular and molecular mechanisms of morphogenesis in disease states such as neural tube defects, cancer, and congenital heart disease. More specifically, one of the genes we are studying, rig-6, is the C. elegans homolog of a human gene that has been implicated in developmental delay associated with 3p deletion syndrome. Another gene we are studying, a RhoGAP called C01F4.2, is the C. elegans homolog of ARHGAP6, a protein implicated in a human skin and eye disease called microphthalmia with linear skin defects. Study of these genes' functions in C. elegans may provide valuable insights into possible functions of the human homologs.

描述（由申请人提供）： 形态发生过程如原肠胚形成、神经胚形成和器官的形成在动物发育中起着关键作用。我们致力于开发C。线虫原肠胚形成作为研究形态发生机制的新模型。我们研究的目标是使用这个模型来理解在形态发生过程中可以定位细胞的一些机制。我们通过将细胞操作与遗传学相结合来研究这些机制，细胞操作在非洲爪蟾和小鸡等系统中取得了成功，遗传学在C.果蝇和斑马鱼。我们的期望是，在一个单一的系统中结合联合收割机遗传学和细胞操作的能力，与现代活的成像方法，研究一个简单的模型的形态发生，将使我们能够作出一些独特的和重要的贡献，了解机制的形态发生。C.线虫原肠胚形成开始于两个内胚层前体细胞的内化。我们的初步研究表明，在这些细胞的顶端肌动球蛋白网络的收缩在其内在化。我们的研究还提供了一套分析方法，可以促进新基因功能的彻底解剖。我们将（1）确定一组粘附蛋白如何调节原肠胚形成中的细胞运动，（2）确定粘附蛋白和细胞内信号分子如何共同促进原肠胚形成，以及（3）基于我们迄今为止鉴定新基因的结果，筛选并追求在上述研究过程中起作用的其他基因。我们希望这个模型可以告知形态发生的细胞和分子机制如何在某些人类疾病中被破坏，最明显的是在神经管缺陷中，如神经管形成和C。秀丽线虫原肠胚形成共有某些细胞和分子机制。项目叙述：我们致力于开发C。秀丽隐杆线虫原肠胚形成是研究形态发生机制的新模型，结合了遗传学、现代活体成像方法和细胞的直接操作。我们研究的总体目标是了解细胞在C. elegans原肠胚形成，以进一步了解包括人类在内的所有动物共同的形态发生机制。我们希望这个简单的模型可以帮助我们了解神经管缺陷、癌症和先天性心脏病等疾病状态下形态发生的细胞和分子机制。更具体地说，我们正在研究的一个基因，rig-6，是C。与3 p缺失综合征相关的发育迟缓有关的人类基因的同源物。我们正在研究的另一个基因，一个名为C01F4.2的RhoGAP，是C。ARHGAP 6是一种与人类皮肤和眼睛疾病有关的蛋白质，称为具有线性皮肤缺陷的小眼症。对这些基因在C.秀丽隐杆线虫可能为人类同源物的可能功能提供有价值的见解。