Mechanisms of C. elegans Gastrulation

描述(由申请人提供)： 原肠形成、神经形成和器官形成等形态发生过程在动物发育中起着至关重要的作用。我们致力于发展线虫原肠形成作为研究形态发生机制的新模型。我们研究的目的是利用这个模型来理解细胞在形态发生过程中定位的一些机制。我们通过将细胞操作与遗传学相结合来探索这些机制，在非洲爪哇和小鸡等系统中取得了成功，在线虫、果蝇和斑马鱼中也取得了成功。我们的期望是，将遗传学和细胞操作结合在一个单一系统中，结合现代实时成像方法来研究形态发生的简单模型，将使我们能够为理解形态发生的机制做出一些独特而重要的贡献。线虫的原肠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，在这些细胞的内化过程中，顶端肌动球蛋白网络发生了收缩。我们的研究还提供了一套分析方法，可以帮助彻底剖析新基因的功能。我们将(1)确定一组黏附蛋白如何调节原肠形成中的细胞运动，(2)确定黏附蛋白和细胞内信号分子如何共同促进原肠形成，以及(3)基于我们的结果识别到目前为止的新基因，筛选和寻找在上述研究过程中发挥作用的其他基因。我们希望这个模型可以揭示在某些人类疾病中，尤其是在神经管缺陷中，形态发生的细胞和分子机制是如何被破坏的，因为神经管形成和线虫原肠发育共享某些细胞和分子机制。项目简介：我们致力于开发线虫原肠形成作为研究形态发生机制的新模型，结合遗传学、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线虫原肠发育中的定位机制，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RIG-6基因之一，是与3p缺失综合征相关的发育延迟有关的人类基因的线虫同源物。我们正在研究的另一种基因是一种名为C01F4.2的RhoGAP基因，它是ARHGAP6的线状皮肤缺陷线状皮肤缺陷的一种蛋白质，与一种名为小眼病的人类皮肤和眼部疾病有关。研究这些基因在线虫中的功能可能会为人类同源物的可能功能提供有价值的见解。

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.