The emergence of collective cell behaviors from intercellular interactions

细胞间相互作用产生集体细胞行为

基本信息

批准号：
10652978
负责人：
Danelle N Devenport
金额：
$ 41.61万
依托单位：
PRINCETON 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：
2022-06-24 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652978
关键词：
Automobile Driving Behavior Biochemical Biological Models Cadherins Cell Adhesion Cells Cellular Structures Complex Congenital Abnormality Congenital Heart Defects Craniorachischises Cytoplasmic Tail Cytoskeletal Modeling Cytoskeleton Developmental Biology Diffusion Embryo Endowment Epidermis Epithelium Exencephalies Failure Generations Genetic Variation Germ Layers Hair Hair follicle structure Human Image Impairment Individual Intercellular Junctions Link Maps Mediating Membrane Modeling Molecular Morphogenesis Morphology Motion Movement Mus Mutation Myosin ATPase Neural Tube Defects Neural tube Organ Organogenesis Outcome P-Cadherin Pathway interactions Pattern Pattern Formation Periodicals Periodicity Phenotype Process Proteins Reaction Regenerative Medicine Resolution Shapes Skin Spinal Dysraphism Structural Congenital Anomalies Structure System Technology Testing Time Tissue Engineering Tissues Vertebrates body system cell behavior cell fate specification cell motility experimental study gastrulation genetic predictors imaging capabilities insight malformation migration mouse genetics novel planar cell polarity prevent progenitor recruit response stem cells superresolution microscopy vertebrate embryos

项目摘要

Project Summary Embryos and organs are shaped by complex collective cell movements involving the coordinated action of thousands of cells over space and time. Impairments in collective cell motion underlie many structural birth defects, the most common of which is the failure to close the neural tube leading to spina bifida, exencephaly, or most severely craniorachischisis. One of the key challenges in developmental biology and tissue engineering is understanding the molecular mechanisms by which cells coordinate their behaviors across thousands of cells to generate large-scale changes in tissue forms through local changes in subcellular organization. The planar cell polarity pathway (PCP) has emerged as a key regulator that organizes individual cell behaviors into large-scale collective cell movements, and is essential for the proper formation of most organ systems in vertebrates. Given the diversity of structures whose morphogenesis relies on PCP, a central challenge is to define a common, unifying set of molecular principals through which PCP acts. Specifically, the molecular links between PCP components and their downstream effectors are poorly defined. Moreover, we do not understand how polarity within individual cells is coordinated into collective, tissue-scale behaviors. Defining these molecular links in detail and connecting them to higher order patterns of collective cell behavior is thus crucial to our basic understanding of tissue morphogenesis. The murine epidermis displays striking spatial and directional patterns, and is an ideal model system to approach these questions. Using newly developed live imaging capabilities, we recently discovered two novel collective cell movements during formation of epithelial placodes in the mammalian skin. These movements bear resemblance to the behaviors that underlie embryonic germ layer formation and gastrulation, suggesting that deeply conserved mechanisms underlie the morphogenesis of very diverse structures. We propose to use the power of the murine epidermis to gain a molecular understanding of these Wnt and PCP-dependent collective cell movements. Specific Aim 1 will define the mechanisms of PCP-mediated force generation and symmetry breaking that drive collective cell motion. Specific Aim 2 will elucidate how patterns of differential cell adhesion promote epithelial motility and prevent cell mixing to compartmentalize collective epithelial movements. Specific Aim 3 will decipher the mechanisms driving epithelial rearrangements during periodic pattern formation. Our findings will define how local, intercellular interactions generate the large-scale collective movements that occur during organogenesis and reveal how structural birth defects arise when these processes go awry.

项目概要胚胎和器官是由复杂的集体细胞运动塑造的，涉及协调行动空间和时间上的数千个细胞。细胞集体运动受损是许多疾病的根源结构性出生缺陷，其中最常见的是神经管未能闭合，导致脊柱裂、无脑畸形或最严重的颅骨劈裂。的主要挑战之一发育生物学和组织工程学正在了解其分子机制细胞协调数千个细胞的行为，从而在组织中产生大规模的变化通过亚细胞组织的局部变化而形成。平面细胞极性通路 (PCP) 成为将个体细胞行为组织成大规模集体细胞的关键调节者运动，对于脊椎动物大多数器官系统的正确形成至关重要。鉴于由于形态发生依赖于 PCP 的结构的多样性，一个中心挑战是定义一个共同的、 PCP 发挥作用的统一分子原理。具体来说，分子之间的联系 PCP 成分及其下游效应器的定义不明确。而且，我们不明白单个细胞内的极性如何协调成集体的、组织规模的行为。定义这些因此，详细的分子联系并将它们与集体细胞行为的更高阶模式连接起来对于我们对组织形态发生的基本理解至关重要。小鼠表皮显示出惊人的空间和方向图案，是理想的模型系统来解决这些问题。利用新开发的实时成像功能，我们最近在上皮基板形成过程中发现了两种新颖的集体细胞运动哺乳动物的皮肤。这些运动与胚胎的行为相似层形成和原肠胚形成，表明深层保守的机制是非常多样化的结构的形态发生。我们建议利用小鼠表皮的力量获得对这些 Wnt 和 PCP 依赖性集体细胞运动的分子理解。具体的目标 1 将定义 PCP 介导的力产生和对称性破坏的机制集体细胞运动。具体目标 2 将阐明差异细胞粘附的模式如何促进上皮运动并防止细胞混合以分隔集体上皮运动。具体的目标 3 将破译周期性模式形成过程中驱动上皮重排的机制。我们的研究结果将定义局部细胞间相互作用如何产生大规模集体器官发生过程中发生的运动，揭示了当这些运动发生时，结构性出生缺陷是如何产生的流程出错。