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: 10038928
• 负责人: Margot L.K. Williams
• 金额: $ 24.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038928
• 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）身体轴的延伸对于健康胎儿的发展至关重要。缺陷 在此过程中，可能导致异常短的胚胎，更重要的是，神经管闭合缺陷 （NTD）。 NTD会影响大约1,000分之一的人类分娩，使其成为最常见的类别之一 先天性先天缺陷。尽管对个人和社会造成了重大负担，但基本的遗传原因 仍然很了解。因此，定义轴扩展的机理可显着贡献 发展生物学的基本研究，对人类健康具有重要意义。前 - 后轴（AP）轴延伸是通过称为收敛的高度保守的形态发生机制发生的 和扩展（C＆E），它采用了两极分化的细胞行为，例如定向迁移和ML细胞 促进身体狭窄的中外侧（ML）的插入，并伴有AP维度的伸长。 在脊椎动物的胚胎中，这发生在胃肠道期间，这是早期的胚胎过程 建立原始细菌层，然后成型为基本的身体计划。 AP的图案 还需要轴，并且在某些情况下也需要轴才能发生C＆E。组织的AP位置身份是 在胃发作之前建立在胚胎轴形成图案的过程中，但是如何将其传达给 尚不理解驱动C＆E的形态发生机制。与组织模式的协调 形态发生仍然是发育生物学中最基本的问题之一。 形态学结节可能在组织模式的界面和 形态发生。在脊椎动物胚胎中，分级的淋巴结信号传导对于诱导内胚层和 中胚层和AP图案，具有较高的淋巴结水平指定更多的背部/前细胞命运。损失 斑马鱼胚胎中的淋巴结信号导致轴向伸展严重降低和开放的神经管，但 同样几乎完整的中胚层缺乏症，使其尚不清楚神经外胚层中的扩展缺陷是否存在 直接归因于淋巴结信号的丧失或间接归因于中胚层的损失。实验证据 提出了中胚层组织C＆E中节点信号的启发性但间接的作用，但是（s）的方式 淋巴结信号传导调节C＆E尚不清楚。在这里，我建议测试节点的假设 信号传导通过其在中胚层规范中间接调节C＆E胃胃运动 图案化并旨在定义淋巴结信号传导的组织，细胞和分子机制 轴扩展的启发性提示。 Nodal在此过程中的作用的表征将大大增加我们的 了解组织模式如何与脊椎动物胚胎中的形态发生协调，并可以帮助 确定NTD的根本原因。