Novel regulators of apical constriction

新型心尖收缩调节器

• 批准号: 8769020
• 负责人: Sergei Sokol
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769020
• 关键词: Actin-Binding Protein; Actomyosin; Apical; Binding; Biochemical; Biological; Birth; Blastopores; Cell Polarity; Cell Shape; Cells; Complementary DNA; Data; Defect; Development; Disease; Embryo; Embryonic Development; Epithelial; Epithelial Cells; Filament; Guanine Nucleotide Exchange Factors; Human; Intercellular Junctions; Knowledge; Malignant Neoplasms; Modeling; Molecular; Molecular Analysis; Movement; Myotonic Dystrophy; Neural Tube Closure; Neural Tube Defects; Pathway interactions; Phosphotransferases; Positioning Attribute; Prevention; Process; Proteins; Regulation; Role; Shapes; Signal Transduction; Strabismus; Surface; Testing; Time; Tissues; Xenopus; base; constriction; expression cloning; gastrulation; in vivo; loss of function; novel; public health relevance; research study; rho

DESCRIPTION (provided by applicant): This proposal concerns molecular mechanisms leading to the formation of apically constricted cells in the vertebrate embryo. Apical constrictio is a process, during which the apical surface of a cell is reduced causing the cell to take on a wedged shape. These coordinated cell shape changes drive many morphogenetic processes throughout development, however, little is known about how apical constriction is regulated at the cellular and molecular level. Our preliminary studies of blastopore formation at the onset of Xenopus gastrulation identified specific candidate regulators of apical constriction and revealed a connection to Wnt signaling. We propose to identify novel components of the apical constriction pathway and evaluate the requirement for the identified candidate molecules in blastopore formation during gastrulation. These experiments will be carried out in Xenopus embryos, which are uniquely suited for biochemical, cell biological and functional analysis of this process in vivo. An unbiased and candidate-based expression cloning approach will be carried out to identify novel regulators of apical constriction and their role in apical constriction will e confirmed in loss-of-function studies. Based on epistatic analysis, these new molecular players will be positioned in a molecular pathway that leads to coordinate spatial regulation of Rho signaling and actomyosin contractility in the apical domains of epithelial cells. The proposed experiments will reconstruct molecular pathways leading to apical constriction in vertebrate epithelial cells during early development and establish a novel function for PCP proteins in apical constriction. These studies will contribute to the knowledge necessary for prevention of birth abnormalities such as neural tube closure defects and will be relevant to human cancer disease.

描述（由申请人提供）：该提案涉及导致脊椎动物胚胎中顶部收缩细胞形成的分子机制。顶端收缩是一个过程，在此过程中细胞的顶端表面减小，导致细胞呈现楔形形状。这些协调的细胞形状变化在整个发育过程中驱动许多形态发生过程，然而，人们对顶端收缩如何在细胞和分子水平上进行调节知之甚少。我们对爪蟾原肠胚形成开始时胚孔形成的初步研究确定了顶端收缩的特定候选调节因子，并揭示了与 Wnt 信号传导的联系。我们建议鉴定顶端收缩途径的新成分，并评估原肠胚形成过程中胚孔形成中对已鉴定候选分子的需求。这些实验将在非洲爪蟾胚胎中进行，该胚胎特别适合对其进行生化、细胞生物学和功能分析。 体内过程。将进行公正且基于候选的表达克隆方法，以确定心尖收缩的新型调节因子，并将在功能丧失研究中证实它们在心尖收缩中的作用。基于上位分析，这些新的分子参与者将被定位在一个分子通路中，该通路导致上皮细胞顶端域中 Rho 信号传导和肌动球蛋白收缩性的协调空间调节。拟议的实验将重建脊椎动物上皮细胞在早期发育过程中导致顶端收缩的分子途径，并建立 PCP 蛋白在顶端收缩中的新功能。这些研究将有助于提供预防出生异常（例如神经管闭合缺陷）所需的知识，并将与人类癌症疾病相关。