Mechanisms of neural tube closure

神经管闭合机制

• 批准号: 10063062
• 负责人: Sergei Sokol
• 金额: $ 37.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063062
• 关键词: Actomyosin; Affect; Anterior; Apical; Behavior; Belief; Biochemical; Biological; Biological Assay; Biotinylation; Brain; Cell membrane; Cell physiology; Cells; Complement; Complex; Congenital Abnormality; Core Protein; Defect; Development; Drosophila genus; Embryo; Epithelial; Experimental Models; Feedback; Genes; Genetic Models; Genetic study; Health; Human; Image; Instruction; Knowledge; Ligands; Light; Mass Spectrum Analysis; Mental disorders; Modeling; Molecular; Morphogenesis; Neural Tube Closure; Neural Tube Defects; Neural tube; Neuraxis; Neuroectoderm; Neuroepithelial; Pathway interactions; Play; Prevention; Process; Protein Analysis; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Protein; Spinal Cord; Surface; System; Testing; Time; Tissues; Wnt proteins; Xenopus; base; experimental study; in vivo Model; loss of function; nervous system development; nervous system disorder; neural plate; neuroepithelium; neuromechanism; novel; planar cell polarity; polarized cell; protease-activated receptor 3; protein complex; receptor; recruit; sensor; vertebrate embryos

Neural tube closure is a morphogenetic process that involves complex behaviors of polarized neural plate cells. With more than 200 genes implicated in this process in genetic models, neural tube abnormalities are among the most common human birth defects. Nevertheless, mechanisms of neural tube closure remain poorly understood and the available vertebrate models are limited. Our preliminary experiments have identified a unique polarization of several proteins in the plane of the Xenopus neural plate and demonstrated that this polarity requires the functions of both planar cell polarity (PCP) and apical-basal polarity proteins. The proposed studies will carry out live imaging of the neural plate using a novel fluorescent sensor. New molecules that physically associate with the PCP complex will be identified using a novel proximity- and complementation- based biotinylation approach combined with mass spectrometry. The involvement of the apical-basal polarity proteins in PCP signaling during neural tube closure will also be evaluated. Xenopus embryos are easily accessible at any developmental stage and are uniquely suited for these studies, allowing rapid analysis of protein localization and function through a combination of biochemical, embryological and cell biological approaches. These experiments will shed light on basic signaling mechanisms that underlie normal development of the central nervous system. The proposed studies are highly relevant to human health, because misregulation of these signaling pathways leads to brain and neural tube defects and a variety of neurological disorders.   .

神经管闭合是一个形态发生过程，涉及复杂的行为 极化神经板细胞。超过 200 个基因参与了这一过程 遗传模型、神经管异常是人类出生时最常见的疾病之一 缺陷。然而，神经管闭合的机制仍然知之甚少， 可用的脊椎动物模型是有限的。我们的初步实验已经确定了 非洲爪蟾神经板平面中几种蛋白质的独特极化 证明这种极性需要平面细胞极性（PCP）的功能 和顶底极性蛋白。拟议的研究将对 使用新型荧光传感器的神经板。物理结合的新分子 与 PCP 复合物的结合将使用一种新的邻近性和互补性来识别 基于生物素化的方法与质谱相结合。的参与 神经管闭合过程中 PCP 信号传导中的顶端-基底极性蛋白也将被 评价。非洲爪蟾胚胎在任何发育阶段都很容易获得，并且 独特地适合这些研究，允许快速分析蛋白质定位和 通过生物化学、胚胎学和细胞生物学的结合发挥作用 接近。这些实验将揭示基本的信号机制 是中枢神经系统正常发育的基础。拟议的研究是 与人类健康高度相关，因为这些信号通路的失调 导致大脑和神经管缺陷以及各种神经系统疾病。   。