Defining Direct and Indirect Roles of Nodal Signaling in Convergence & Extension

定义节点信令在收敛中的直接和间接作用

基本信息

批准号：
10292449
负责人：
Margot L.K. Williams
金额：
$ 24.4万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292449
关键词：
Activins Affect Animal Cap Anterior Bioinformatics Birth Blastoderm Candidate Disease Gene Cell Polarity Cell physiology Cells Cessation of life Characteristics Complex Congenital Abnormality Cues Data Defect Development Developmental Biology Dimensions Dorsal Drosophila genus Ectoderm Embryo Embryology Embryonic Development Endoderm Exhibits Exposure to Failure Fetus Gene Expression Genetic Germ Layers Head Health Human Individual Instruction Lead Ligands Mesoderm Mesoderm Cell Modeling Molecular Morphogenesis Movement Neural Tube Closure Neural Tube Defects Neural tube Neuroectoderm Nodal Paraxial Mesoderm Pattern Phase Play Population Positioning Attribute Process Proteins Role Signal Transduction Societies Specific qualifier value Spinal Dysraphism Tail Testing Tissues Transplantation Vertebrates Work Xenopus Zebrafish cell behavior cell fate specification differential expression disability gain of function gastrulation intercalation migration morphogens mutant notochord planar cell polarity polarized cell transcriptome sequencing vertebrate embryos

项目摘要

Project Summary Extension of the anterior-posterior (head to tail) body axis is critical to development of a healthy fetus. Defects in this process can result in abnormally short embryos, and more importantly, neural tube closure defects (NTDs). NTDs affect approximately 1 in 1,000 human births, making them one of the most common classes of congenital birth defects. Despite the significant burden to individuals and society the underlying genetic causes remain still poorly understood. Therefor, defining the mechanisms of axis extension contributes significantly to the fundamental study of developmental biology and has important implications in human health. Anterior- posterior (AP) axis extension occurs via a highly conserved morphogenetic mechanism called convergence and extension (C&E), which employs polarized cell behaviors such as directed migration and ML cell intercalation to drive mediolateral (ML) narrowing of the body accompanied by elongation in the AP dimension. In vertebrate embryos, this occurs during gastrulation, the early embryonic process during which the three primordial germ layers are established and then shaped into a rudimentary body plan. Patterning of the AP axis is also required, and in some cases sufficient, for C&E to occur. AP positional identity of a tissue is established during embryonic axis patterning prior to the onset of gastrulation, but how this is communicated to the morphogenetic machinery that drives C&E is not understood. This coordination of tissue patterning with morphogenesis remains one of the most fundamental questions in developmental biology. The morphogen Nodal likely occupies a vital position at the interface of tissue patterning and morphogenesis. In vertebrate embryos, graded Nodal signaling is essential for induction of endoderm and mesoderm and AP patterning, with higher Nodal levels specifying more dorsal/anterior cells fates. Loss of Nodal signaling in zebrafish embryos results in severely reduced axial extension and an open neural tube, but also nearly complete mesoderm deficiency, making it unclear whether extension defects in the neuroectoderm are due directly to the loss of Nodal signaling or indirectly to the loss of mesoderm. Experimental evidence suggests an instructive yet indirect role of Nodal signaling during C&E of mesodermal tissues, but the way(s) by which Nodal signaling regulates C&E is unknown. Here, I propose to test the hypothesis that Nodal signaling regulates C&E gastrulation movements indirectly via its role in mesoderm specification and patterning, and aim to define the tissue, cellular, and molecular mechanisms by which Nodal signaling provides instructive cues for axis extension. Characterization of Nodal's role in this process will significantly increase our understanding of how tissue patterning is coordinated with morphogenesis in vertebrate embryos and can help to identify the underlying causes of NTDs.

项目概要前后（头到尾）身体轴的延伸对于健康胎儿的发育至关重要。缺陷在这个过程中会导致异常短的胚胎，更重要的是，神经管闭合缺陷（被忽视的热带病）。 NTD 影响大约千分之一的人类出生，使其成为最常见的类别之一先天性出生缺陷。尽管对个人和社会造成重大负担，但潜在的遗传原因仍然知之甚少。因此，定义轴延伸的机制对发育生物学的基础研究，对人类健康具有重要影响。前- 后轴 (AP) 延伸通过高度保守的形态发生机制（称为收敛）发生和延伸 (C&E)，它采用极化细胞行为，例如定向迁移和 ML 细胞插层驱动身体的内侧（ML）变窄，同时伴随着 AP 维度的伸长。在脊椎动物胚胎中，这种情况发生在原肠胚形成期间，即早期胚胎过程，在此期间，三个原始胚层建立，然后形成基本的身体结构。 AP 的图案化轴对于收容和教育的发生也是必需的，并且在某些情况下就足够了。组织的 AP 位置标识是在原肠胚形成之前的胚胎轴模式中建立，但是这是如何传达给驱动 C&E 的形态发生机制尚不清楚。这种组织图案的协调形态发生仍然是发育生物学中最基本的问题之一。形态发生素 Nodal 可能在组织图案化和组织形态形成的界面上占据重要位置。形态发生。在脊椎动物胚胎中，分级节点信号对于内胚层和内胚层的诱导至关重要。中胚层和 AP 模式，较高的节点水平指定更多的背侧/前部细胞命运。损失斑马鱼胚胎中的节点信号传导导致轴向延伸严重减少和神经管开放，但是中胚层几乎完全缺乏，因此尚不清楚神经外胚层是否存在延伸缺陷直接归因于节点信号传导的丧失或间接归因于中胚层的丧失。实验证据表明 Nodal 信号在中胚层组织的 C&E 过程中具有指导性但间接的作用，但方式 Nodal 信号传导通过何种方式调节 C&E 尚不清楚。在这里，我建议检验以下假设：Nodal 信号传导通过其在中胚层规范中的作用间接调节 C&E 原肠胚形成运动模式，旨在定义节点信号提供的组织、细胞和分子机制轴延伸的指导性线索。描述节点在此过程中的作用将显着提高我们的了解脊椎动物胚胎中组织模式如何与形态发生相协调，可以帮助确定 NTD 的根本原因。