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

基本信息

批准号：
10708839
负责人：
Xiaoyan Zheng
金额：
$ 32.3万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10708839
关键词：
Affect Biochemical 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 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 TGF Beta Signaling Pathway 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

项目摘要

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.

项目概要/摘要左右（LR）不对称的建立是内部正确定位所需的关键事件。器官。人类 LR 轴形成缺陷会导致心脏、脉管系统、肺和肠道的出生缺陷道。导致 LR 不对称性产生的基因网络在不同群体中高度保守脊椎动物。在小鼠中，建立 LR 轴的初始不对称信号在节点中确定为纤毛驱动的向左流体流动（节点流动）。然后这些信号被转移到左侧板中胚层（LPM），它将经历不对称的器官形态发生。 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，并经过很长的距离到达左 LPM，它启动瞬态自动调节电路（涉及 Nodal 和 Lefty），传播 Node 信号传导并激活左侧决定簇配对样同源域转录的表达因子 2 (Pitx2)。 Hedgehog (Hh) 信号通路在 LR 模式形成中也发挥着至关重要的作用。在鼠标中， Hh 信号传导需要建立分隔胚胎左侧和右侧的中线，以及激活 LPM 中的节点相关自动调节电路。然而，Hh 的机制信号传导调节 LPM 的节点响应能力尚不清楚。因此，识别 Hh 和 TGF-b 途径的特定汇聚点对于理解深入机制至关重要基础 LR 不对称测定，从而提供更好的诊断、预防和治疗干预针对 LR 不对称相关的出生缺陷。我们最近发现 Hh 通路的一个新靶点，神经元衍生神经营养因子 (Ndnf)，调节小鼠的轴向旋转和肠循环。在拟议的工作中，我们将纳入生物化学、分子和遗传学方法（目标 1）评估来源，（目标 2）确定转录调控，以及（目标 3）研究 LR 中 Ndnf 的潜在分子机制决心。