Mechanisms of C. elegans Gastrulation

线虫原肠胚形成的机制

基本信息

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
项目类别：
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

项目摘要

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）：原肠胚形成、神经形成和器官成形等形态发生过程在动物发育中发挥着至关重要的作用。我们致力于开发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该模型来了解在形态发生过程中定位细胞的一些机制。我们通过将细胞操作（在非洲爪蟾和小鸡等系统中取得成功）与遗传学（在秀丽隐杆线虫、果蝇和斑马鱼中取得成功）相结合来研究这些机制。我们的期望是，将遗传学和细胞操作结合在一个系统中，再加上现代实时成像方法来研究简单的形态发生模型，将使我们能够为理解形态发生机制做出一些独特而重要的贡献。线虫原肠胚形成始于两个内胚层前体细胞的内化。我们的初步研究表明这些细胞的顶端肌动球蛋白网络在其内化过程中发生收缩。我们的研究还提供了一套可以促进新基因功能彻底剖析的分析方法。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）根据我们迄今为止识别新基因的结果，筛选并寻找在上述研究过程中发挥作用的其他基因。我们期望该模型能够告知形态发生的细胞和分子机制在某些人类疾病中如何被破坏，尤其是在神经管缺陷中，因为神经管形成和秀丽隐杆线虫原肠胚形成具有某些细胞和分子机制。项目叙述：我们致力于开发线虫原肠胚形成作为研究形态发生机制的新模型，结合遗传学、现代实时成像方法和细胞直接操作。我们研究的总体目标是了解线虫原肠胚形成中细胞的定位机制，进一步了解包括人类在内的所有动物常见的形态发生机制。我们期望这个简单的模型可以帮助我们理解神经管缺陷、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，我们正在研究的基因之一 rig-6 是线虫中人类基因的同源物，该基因与 3p 缺失综合征相关的发育迟缓有关。我们正在研究的另一个基因，称为 C01F4.2 的 RhoGAP，是 ARHGAP6 的秀丽隐杆线虫同源物，ARHGAP6 是一种与人类皮肤和眼部疾病（称为小眼症并伴有线性皮肤缺陷）有关的蛋白质。对秀丽隐杆线虫中这些基因功能的研究可能为人类同源物的可能功能提供有价值的见解。