Developmental Circuits in Gastrulation and Neurulation

原肠胚形成和神经形成的发育回路

• 批准号: 6847127
• 负责人: MARC Wallace KIRSCHNER
• 金额: $ 53.74万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-06 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847127
• 关键词: Chordata; Xenopus; Xenopus oocyte; aquatic organism; biochemical evolution; biological signal transduction; cell cell interaction; cell differentiation; cell free system; cell migration; cell motility; confocal scanning microscopy; developmental genetics; gene expression; gene interaction; genetic regulation; genetic transcription; histogenesis; mesoderm; microtubules; mitogen activated protein kinase; neural plate /tube; protein structure function; transcription factor

DESCRIPTION (provided by applicant): Gastrulation is a process where the provisional spatial organization of the egg is transformed into the definitive body plan of the adult. In vertebrate organisms, the major developmental mechanism for establishing the body plan during gastrulation is the Spemann Organizer. The Organizer has no obvious parallels in the major invertebrate phyla, although it is present in invertebrate Chordates, like Ascidians. The major features of the Organizer in gastrulation are the specification of cell behaviors, required to create the adult body plan, the existence of several key signaling systems (whose origins in several cases predate the vertebrate emergence), and the coordinated secretion of proteins that regulate and, in particular, inhibit several pathways. We have taken three ambitious well defined approaches to gastrulation. In the first, we try to understand how the gene brachyury controls the decision of whether cells migrate, as they do in head mesoderm or undergoes a multicellular sorting behavior called convergent extension, in the chordamesoderm. We plan to examine genes downstream of brachyury that control adhesion to fibronectin and cell motility. As part of these studies, we will take a closer look at the mechanism of cell polarization in multicellular populations by confocal microscopy and, in particular, the role of microtubules in polarization. In the second, we try to understand how the Wnt signaling pathway interprets and processes signals, by reconstituting large portions of it in cell free extracts from Xenopus eggs. We will look particularly carefully at the role of Casein Kinase 1 and the mechanism of Axin degradation. We will also look at another important pathway, the MAP kinase pathway as to how it processes signals, making quantitative measurements of rates and fluxes and modeling it mathematically. Finally, we will step as far back as we can from vertebrate gastrulation to a sister phylum of Chordates, Hemichordates, to examine whether there are features of the Organizer that can be identified that may lead to an understanding of how gastrulation in Chordates became the major mechanism for organizing the body plan. Our major approach here is to examine the early embryology of the acorn worm, Saccoglossus kowalevskii, and identify genes which in vertebrates play a major role in the Organizer.

描述（由申请人提供）：原肠胚形成是卵子的临时空间组织转变为成人最终身体规划的过程。在脊椎动物中，原肠胚形成期间建立身体计划的主要发育机制是斯佩曼组织者。组织者在主要无脊椎动物门中没有明显的相似之处，尽管它存在于无脊椎动物脊索动物中，如海鞘类。原肠胚形成过程中组织者的主要特征是细胞行为的规范，这是创建成人身体计划所需的，几个关键信号系统的存在（在某些情况下其起源早于脊椎动物的出现），以及调节蛋白质的协调分泌特别是，抑制多种途径。我们采取了三种雄心勃勃且明确的原肠胚形成方法。首先，我们试图了解基因brachyury如何控制细胞是否迁移的决定，就像它们在头部中胚层中所做的那样，还是在脊索中胚层中经历称为聚合延伸的多细胞分类行为。我们计划检查brachyury下游控制纤连蛋白粘附和细胞运动的基因。作为这些研究的一部分，我们将通过共聚焦显微镜仔细研究多细胞群体中的细胞极化机制，特别是微管在极化中的作用。在第二部分中，我们尝试通过在非洲爪蟾卵的无细胞提取物中重建 Wnt 信号通路的大部分信号，来了解 Wnt 信号通路如何解释和处理信号。我们将特别仔细地研究酪蛋白激酶 1 的作用和轴蛋白降解的机制。我们还将研究另一个重要的途径，即 MAP 激酶途径，了解它如何处理信号、定量测量速率和通量并对其进行数学建模。最后，我们将尽可能从脊椎动物的原肠胚形成追溯到脊索动物的姐妹门半索动物门，以检查是否存在可以识别的组织者特征，这些特征可能有助于理解脊索动物的原肠胚形成如何成为主要的动物门。组织机构计划的机制。我们在这里的主要方法是检查橡子蠕虫（Saccoglossus kowalevskii）的早期胚胎学，并鉴定在脊椎动物中在组织者中起主要作用的基因。