Linking Hedgehog and Nodal/TGF-beta signaling in the establishment of left-right asymmetry

连接 Hedgehog 和 Nodal/TGF-β 信号传导以建立左右不对称

• 批准号: 10503905
• 负责人: Xiaoyan Zheng
• 金额: $ 30.49万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503905
• 关键词: Affect; Biochemical; Biochemical Genetics; Cilia; Competence; Congenital Abnormality; Defect; Development; Developmental Biology; Diagnosis; Drosophila genus; Embryo; Embryonic Development; Erinaceidae; Event; Extracellular Matrix Proteins; Fibronectins; Gene Expression; Generations; Genes; Growth; Heart Abnormalities; Homologous Gene; Human; Intestines; Knowledge; Lateral; Left; Limb Bud; Link; Location; Lung; Mediating; Mesoderm; Molecular; Molecular Genetics; Morphogenesis; Mus; Neural tube; Neurons; Nodal; Organ; Pathway interactions; Pattern; Play; Positioning Attribute; Regulation; Research; Role; Rotation; Side; Signal Pathway; Signal Transduction; Site; Source; Structure; Testing; Therapeutic Intervention; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factors; Travel; Vertebrates; Wing; Work; disability; early embryonic stage; fluid flow; gene network; genetic approach; homeodomain; neuron loss; neurotrophic factor; novel; preventive intervention; response; secretory protein; smoothened signaling pathway; tool; transcription factor; vertebrate embryos

Project summary/abstract The establishment of left-right (LR) asymmetry is a critical event required for the correct positioning of internal organs. Defects in human LR axis formation cause birth defects of the heart, vasculature, lungs, and intestinal tract. The gene network contributing to the generation of LR asymmetry is highly conserved across vertebrates. In the mouse, the initial asymmetric signals establishing LR axis are determined in the node by cilia-driven leftward fluid flow (nodal flow). These signals are then transferred to the left lateral plate mesoderm (LPM), which will undergo asymmetric organ morphogenesis. Nodal, a secretory protein that belongs to the transforming growth factor-b (TGF-b) superfamily, is expressed in the node and travels a long distance to the left LPM, where it initiates a transient auto-regulatory circuit (involving Nodal and Lefty) that propagates Nodal signaling and activates expression of the left-sided determinant Paired-Like Homeodomain transcription factor 2 (Pitx2). The Hedgehog (Hh) signaling pathway also plays a crucial role in LR patterning. In the mouse, Hh signaling is required to establish the midline that separates the left and right sides of the embryo, as well as to activate the Nodal-dependent auto-regulatory circuit in the LPM. However, the mechanism by which Hh signaling regulates the competence of the LPM for Nodal response is not well understood. Thus, identifying the specific convergence point of the Hh and TGF-b pathways is critical for understanding the in-depth mechanism underlying LR asymmetry determination, and therefore to provide better diagnosis, preventive and therapeutic intervention against LR asymmetry-related birth defects. We recently found that a novel target of the Hh pathway, Neuron-Derived Neurotrophic Factor (Ndnf), regulates axial rotation and intestinal looping in the mouse. In the proposed work, we will incorporate biochemical, molecular, and genetic approaches to (Aim 1) assess the source, (Aim 2) determine the transcriptional regulation, and (Aim 3) investigate the underlying molecular mechanisms of Ndnf in LR determination.

项目摘要/摘要 建立左右（LR）不对称是内部正确定位所需的关键事件 器官。人体LR轴形成缺陷会导致心脏，脉管系统，肺和肠的出生缺陷 道。导致LR不对称产生的基因网络在跨越高度保守 脊椎动物。在小鼠中，建立LR轴的初始不对称信号在节点中确定 纤毛驱动的向左流动流（节点流）。然后将这些信号转移到左侧板中的中胚层 （lpm），它将发生不对称器官形态发生。 Nodal，一种分泌蛋白，属于 转化生长因子-B（TGF-B）超家族在节点中表达，并长途旅行 左LPM，启动瞬态自动调节电路（涉及节点和左撇子），该电路传播了节点 信号传导和激活左侧决定簇成对的同源域转录的表达 因子2（PITX2）。刺猬（HH）信号通路在LR模式中也起着至关重要的作用。在鼠标中， 需要HH信号传导才能建立将胚胎的左侧和右侧分开的中线以及 激活LPM中的节点依赖性自动调节电路。但是，HH的机制 信号传导调节LPM对淋巴结响应的能力尚不清楚。因此，识别 HH和TGF-B途径的特定收敛点对于理解深度机制至关重要 基础LR不对称确定，因此提供更好的诊断，预防和治疗 干预 LR不对称相关的先天缺陷。 我们最近发现，HH途径，神经元衍生的神经营养因子（NDNF）的新目标， 调节小鼠中的轴向旋转和肠循环。在拟议的工作中，我们将合并 生化，分子和遗传方法（目标1）评估来源，（目标2）确定 转录调控，（目标3）研究NDNF在LR中的基本分子机制 决心。