Vangl2 function in mammalian convergent extension

Vangl2 在哺乳动物会聚延伸中的功能

基本信息

批准号：
9889144
负责人：
Ann E Sutherland
金额：
$ 32.45万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889144
关键词：
Abdomen Address Adherens Junction Adhesions Adhesives Adult Affect Alleles Apical Birth CELSR1 gene Cadherins Cell Polarity Cells Cellular Morphology Characteristics Chordata Complex Confocal Microscopy Congenital Abnormality Core Protein Craniorachischises Defect Development Drosophila genus Dsh protein E-Cadherin Elements Embryo Embryonic Development Epithelial Epithelial Cells Epithelium Exhibits Eye Failure Fetus Fishes Frequencies Future Genes Genetic Genetic Models Hair Head Heterozygote Human Human Development Image Infant Infant Mortality Lead Medical Membrane Proteins Mesoderm Modeling Mus Mutant Strains Mice Mutation N-Cadherin Neural Tube Closure Neural Tube Defects Neural tube Neurons Paraxial Mesoderm Pathway interactions Phenotype Process Proteins Publishing Rana Regulation Resolution Role Set protein Shapes Signal Pathway Signal Transduction Skeleton Spinal Cord Surface Syndrome Tail Testing Time Tissue membrane Tissues Variant Vertebrates Wing Work base cell behavior constriction convergent extension disability experimental study fly hindbrain insight intercalation loss of function mortality mutant neurodevelopment paralogous gene planar cell polarity polarized cell public health relevance relating to nervous system rib bone structure spine bone structure

项目摘要

DESCRIPTION (provided by applicant): Elongation of the body in the head-to-rump axis is a fundamental aspect of vertebrate embryogenesis whose failure is associated with neural tube defects and embryonic mortality in fish, frogs, mice, and humans. In humans, neural-tube defects affect 1 to 2 infants per 1000 births and lead in the worst cases to early infant mortality and in less severe cases to lifelong medical treatment and disability. Elongation occurs by a process in which cells of the future spinal cord and associated mesoderm actively move (intercalate) between one another to form narrower, longer tissues (called "convergence and extension' or CE), which elongates the embryonic body. In vertebrates, this "mediolateral" cell intercalation is dependent on the non-canonical Wnt planar cell polarity (Wnt/PCP) pathway, which consists of a core set of proteins thought to polarize cells within the plane of the tissue: the membrane proteins Celsr, Frizzled (Frz), and Van Gogh-like (Vangl), and the intracellular proteins Dishevelled (Dvl) and Prickle (Pk). Mice carrying mutations in the genes Celsr1, Frz3/6, Vangl2 and Dvl1/2 as well as Ptk7 and Scrib, two genes not directly associated with Wnt/PCP, exhibit a characteristic phenotype of a short, wide body axis, an open neural tube, and lethality at birth. One model of genetic regulation of cell intercalation focuses on polarized remodeling of junctions at the apical surfaces of epithelial cells and the other on polarized "crawling" of non-epithelial cells. Use of high resolution, multi-plane time-lapse confocal microscopy to simultaneously image both apical junctional and the basolateral surfaces of the neural epithelium of normal mouse embryos as compared to Vangl2 and Ptk7 mutants, showed that apical cell boundary rearrangement and polarized basolateral protrusive activity must act cooperatively for mediolateral intercalation and CE to occur. Neural cells lacking Ptk7 fail to planarly polarize both apical and basolateral cell behaviors and they intercalate vigorously but randomly. Surprisingly, polarity of both basal protrusive activity and apical boundary rearrangement is maintained in the Vangl2 mutant, and instead the frequency of apical neighbor exchange is significantly diminished. These unexpected observations, and other, published variations in phenotypes of Wnt/PCP mutant genes across the chordates, suggest that Wnt/PCP function has diversified across species and tissues. The proposed experiments explore this possibility by determining how Vangl and the related protein Scrib regulate neural cell behavior. First, because the loss of Vangl2 does not affect planar polarity of cell behavior, we will test whether the paralog Vangl1 can compensate to generate polarity in the absence of Vangl2, or whether polarity is regulated instead by a complex of Vangl2 and Scrib. Second, because Vangl2 specifically affects apical junctional rearrangement, we will test whether it affects the dynamics of cadherin-based adhesion in neural cell intercalation. The results will provide broader and deeper insights into the cellular behaviors regulated by the Wnt/PCP pathway during neural development, and how they coordinate elongation and closure of the neural tube.

描述（通过应用提供）：从头到头轴中身体的伸长是脊椎动物胚胎发生的基本方面，其失败与鱼类，青蛙，小鼠和人类的神经管缺陷和胚胎死亡率有关。在人类中，神经管缺陷会影响每1000个出生的1至2个婴儿，并在最坏的情况下导致早期婴儿死亡率在不太严重的情况下，终身治疗和残疾。伸长是通过一个过程发生的过程，在一个过程中，未来的脊髓和相关中胚层的细胞相互积极移动（插度），形成更狭窄，更长的组织（称为“收敛和扩展”或CE），从而延长了胚胎的身体。在脊椎动物中，这种“内侧”细胞相互作用依赖于平面的PR PAR PRECITS CONTARY PR PRAN PARTITY（Wnt PC）contery（Wnt PC），Wnt PC（Wnt PC）（Wnt PC）（Wnt PC）（Wnt PC）（Wnt PC）（Wnt PC）。一组蛋白质被认为在组织平面内偏振细胞：膜蛋白摄氏，卷曲（FRZ）和van gogh样（Vangl），以及细胞内蛋白质的味道（DVL）和prike蛋白（pk）和pK中的小鼠以及frz3/6，Vang2和dvand and vang2 and vang2 and vang2和dvand。 SCRIB是两个与Wnt/PCP直接相关的基因，暴露了一个短体轴的特征表型，开放的神经管和出生时的致死性。与Vangl2和PTK7突变体相比，使用高分辨率的多平面延时共焦显微镜同时形象形象正常小鼠胚胎的神经上皮的基础外侧表面和基底外侧表面，这表明顶端细胞重排和极性基础外侧的高度固定活性和甲型级别的近极性活性和甲型化的均匀分别是对的。缺乏PTK7的神经细胞无法平稳地使根尖和基底外侧细胞行为偏振，并且它们会剧烈但随机地插入。令人惊讶的是，基本突出活性和顶端边界重排的极性在Vangl2突变体中保持不变，而顶端邻居交换的频率显着降低。这些意外的观察结果以及其他发表的在整个弦的Wnt/PCP突变基因表型中的变化，表明Wnt/PCP功能在物种和组织中都有多样化。提出的实验通过确定VANGL和相关蛋白SCRIB如何调节神经元细胞行为来探讨这种可能性。首先，由于vangl2的丧失不会影响细胞行为的平面极性，因此我们将测试旁系同源物vangl1是否可以补偿在没有vangl2的情况下产生极性，还是通过Vangl2和Scrib的复合物调节极性。其次，由于vangl2特别影响了顶端连接重排，因此我们将测试它是否影响基于钙粘着蛋白的粘合剂在神经元细胞插入中的动力学。结果将为神经元发育过程中由WNT/PCP途径调节的细胞行为提供更广泛的见解，以及它们如何协调神经管的伸长和闭合。