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

项目摘要 前-后(头到尾)体轴的伸展对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 (NTDS)。NTDS影响大约1,000名人类新生儿，使其成为最常见的 先天出生缺陷。尽管给个人和社会带来了沉重的负担，但潜在的遗传原因 人们对此仍然知之甚少。因此，定义轴延伸的机制对于 是发育生物学的基础研究，对人类健康具有重要意义。前部- 后(AP)轴的延伸是通过一种被称为收敛的高度保守的形态发生机制来实现的 以及扩展(C&E)，其采用定向迁移和ML信元等极化细胞行为 插入导致椎体内外侧(ML)狭窄，并伴有AP维度的延长。 在脊椎动物胚胎中，这发生在原肠形成期间，在这一早期胚胎过程中，三个 原始胚层被建立起来，然后形成一个基本的身体计划。AP的图案化 对于C&E的发生，AXIS也是必需的，在某些情况下是充分的。组织的AP位置标识是 在原肠形成开始之前的胚轴构型期间建立的，但这是如何被传达到 推动C&E的形态发生机制尚不清楚。这种组织图案化与 形态发生是发育生物学中最基本的问题之一。 形成结节可能在组织图案化和组织图案化的界面上占据重要位置 形态发生。在脊椎动物胚胎中，分级结节信号是诱导内胚层和 中胚层和AP图案化，较高的结节水平指定更多的背侧/前部细胞的命运。损失 斑马鱼胚胎中的结节信号导致轴向伸展严重减少和神经管开放，但 也几乎完全的中胚层缺陷，使得不清楚神经外胚层是否存在延伸性缺陷 直接由于Nodal信号的丢失或间接由于中胚层的丢失。实验证据 提示Nodal信号在中胚层组织的C&E过程中具有指导性但又间接的作用，但其方式(S) Nodal信号通过什么来调节C&E尚不清楚。在这里，我建议检验诺达尔的假设 信号转导通过其在中胚层发育中的作用间接调节C&E的原肠运动。 图案化，并旨在定义Nodal信号提供的组织、细胞和分子机制 轴延伸的指导性提示。对节点在这一过程中的作用的描述将显著增加我们的 了解脊椎动物胚胎的组织模式与形态发生是如何协调的，这有助于 以找出非专利疾病的根本原因。

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.