The emergence of collective cell behaviors from intercellular interactions

细胞间相互作用产生集体细胞行为

• 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
• 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

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.

项目摘要 胚胎和器官是由涉及协调作用的复杂集体细胞运动来塑造的 在空间和时间上成千上万个单元。集体细胞运动的损害是许多 结构性先天缺陷，其中最常见的是未能关闭导致的神经管 脊柱裂，外脑或最严重的颅骨。主要挑战之一 发育生物学和组织工程正在理解分子机制 细胞在数千个细胞中协调其行为，以产生组织的大规模变化 通过亚细胞组织的局部变化形成。平面细胞极性途径（PCP）具有 成为关键调节器，将单个细胞行为组织成大规模的集体单元 运动，对于脊椎动物中大多数器官系统的正确形成至关重要。鉴于 形态发生依赖PCP的结构的多样性，一个核心挑战是定义一个共同的， 统一PCP作用的分子原理。具体而言，分子联系 PCP组件及其下游效应子的定义很差。而且，我们不明白 单个细胞内的极性如何协调为集体组织尺度行为。定义这些 因此 对于我们对组织形态发生的基本理解至关重要。 鼠表皮显示出惊人的空间和方向模式，是理想的模型 解决这些问题的系统。使用新开发的实时成像功能，我们最近 在形成上皮位置的过程中发现了两个新型的集体细胞运动 哺乳动物皮肤。这些运动与胚胎细菌的行为相似 层的形成和胃分解，表明深处保守的机制是 非常多样化的结构的形态发生。我们建议利用鼠表皮的力量 对这些Wnt和PCP依赖性集体细胞运动获得分子理解。具体的 AIM 1将定义PCP介导的力产生和对称破坏的机制 集体细胞运动。特定的目标2将阐明差分细胞粘附的模式如何促进 上皮运动，并防止细胞混合以使集体上皮运动分裂。具体的 AIM 3将破译在周期性模式形成期间驱动上皮重排的机制。 我们的发现将定义本地，细胞间的相互作用如何产生大规模集体 在器官发生过程中发生的运动，并揭示了结构性出生缺陷的发生 流程出了问题。