Vangl2 function in mammalian convergent extension

Vangl2 在哺乳动物会聚延伸中的功能

• 批准号: 9247221
• 负责人: Ann E Sutherland
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/9247221
• 关键词: Abdomen; Address; Adherens Junction; Adhesions; Adhesives; Adult; Affect; Alleles; Apical; Behavior; 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

 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.