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

• 批准号: 9769071
• 负责人: Margot L.K. Williams
• 金额: $ 9.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2019-11-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769071
• 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; Expression Profiling; 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

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.

项目摘要 前后（头到尾）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 （NTD）。NTD影响约1/1，000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的重大负担， 仍然知之甚少。因此，确定轴延伸的机制有助于 发育生物学的基础研究，对人类健康有重要意义。前- 后（AP）轴延伸通过高度保守的形态发生机制，称为收敛 和扩展（C&E），它采用极化细胞行为，如定向迁移和ML细胞 插入以驱动身体的内外侧（ML）变窄，伴随着AP维度的延长。 在脊椎动物胚胎中，这发生在原肠胚形成期间，在此期间，三个胚胎发育的早期胚胎过程 原始胚层建立起来，然后形成一个基本的身体平面。AP的图案化 轴也是需要的，在某些情况下，C&E的发生是足够的。组织的AP位置标识是 在原肠胚形成开始之前的胚胎轴模式期间建立，但这是如何传递给 驱动C&E的形态发生机制尚不清楚。这种组织模式的协调与 形态建成仍然是发育生物学中最基本的问题之一。 形态发生素Nodal可能在组织图案化的界面处占据重要位置， 形态发生在脊椎动物胚胎中，分级的Nodal信号传导对于内胚层的诱导是必不可少的， 中胚层和AP图案化，更高的Nodal水平指定更多的背/前细胞命运。损失 斑马鱼胚胎中的节点信号导致轴向延伸严重减少和神经管开放， 也几乎完全的中胚层缺陷，使得目前还不清楚是否在神经外胚层的延伸缺陷， 是直接由于Nodal信号传导的损失或间接由于中胚层的损失。实验证据 提示在中胚层组织的C&E期间Nodal信号传导的指导性但间接的作用，但方式 Nodal信号通过何种方式调节C&E尚不清楚。在这里，我建议测试的假设， 信号传导通过其在中胚层特化中的作用间接调节C&E原肠胚形成运动， 模式化，旨在定义Nodal信号提供的组织，细胞和分子机制 轴延伸的指导性线索。Nodal在这一过程中的作用的表征将大大增加我们的 了解脊椎动物胚胎中组织模式如何与形态发生协调， 找出NTD的根本原因。