The emergence of collective cell behaviors from intercellular interactions

项目摘要 胚胎和器官是由复杂的集体细胞运动形成的，这些运动涉及协调的行动 数以千计的细胞在空间和时间上。集体细胞运动的损害是许多 结构性出生缺陷，其中最常见的是未能关闭神经管导致 脊柱裂，脑外畸形，或最严重的颅裂。面临的主要挑战之一 发育生物学和组织工程学正在理解分子机制， 细胞在数千个细胞之间协调其行为，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形成。平面细胞极性途径(PCP)具有 成为将个体细胞行为组织成大规模集体细胞的关键调节器 运动，对脊椎动物的大多数器官系统的正常形成是必不可少的。给定 其形态发生依赖于PCP的结构的多样性，一个中心挑战是定义一个共同的， 一套统一的分子原理，PCP通过这些原理起作用。具体地说，分子之间的联系 五氯苯酚成分及其下游效应器的定义不明确。此外，我们不理解 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 详细的分子连接，并将它们连接到集体细胞行为的更高顺序模式 对我们对组织形态发生的基本理解至关重要。 小鼠表皮具有明显的空间和方向性，是一个理想的模型。 系统来处理这些问题。使用新开发的实时成像功能，我们最近 在上皮性安慰剂的形成过程中发现了两种新的集体细胞运动 哺乳动物的皮肤。这些运动与构成胚胎胚胎的行为相似 层的形成和原肠形成，这表明深度保守的机制是 非常多样化的结构的形态发生。我们建议使用小鼠表皮的力量来 从分子上了解这些依赖Wnt和PCP的集体细胞运动。特定的 目标1将定义PCP介导力产生和对称性破坏的机制 集体细胞运动。特定目标2将阐明不同的细胞黏附模式如何促进 上皮运动，并防止细胞混合，以划分集体上皮运动。特定的 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。 我们的发现将定义局部的、细胞间的相互作用如何产生大规模的集体 器官发生过程中发生的运动，并揭示结构性出生缺陷是如何在这些 流程出了问题。

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.