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， 在空间和时间上成千上万的细胞。集体细胞运动的损伤是许多 结构性出生缺陷，其中最常见的是未能关闭神经管， 脊柱裂、露脑畸形或最严重的颅脊柱裂。的关键挑战之一 发育生物学和组织工程学是了解分子机制， 细胞在数千个细胞中协调它们的行为， 通过亚细胞组织的局部变化形成。平面细胞极性途径（PCP） 作为一个关键的调节器出现，将单个细胞行为组织成大规模的集体细胞 运动，并为脊椎动物中大多数器官系统的正确形成所必需。鉴于 形态发生依赖PCP的结构多样性，一个核心挑战是定义一个共同的， 一套统一的分子原理，五氯苯酚通过这些原理起作用。具体来说， 五氯苯酚组分及其下游效应物定义不清。此外，我们不明白 个体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，详细地研究分子联系并将它们与集体细胞行为的更高级模式联系起来， 对我们理解组织形态发生至关重要。 小鼠表皮显示出显著的空间和方向模式，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 发现了两种新的集体细胞运动过程中形成的上皮基板在 哺乳动物的皮肤这些运动与胚胎的行为相似 层的形成和原肠胚形成，这表明，深度保守的机制， 非常不同的结构的形态发生。我们建议利用小鼠表皮的力量， 获得这些Wnt和PCP依赖的集体细胞运动的分子理解。具体 目标1将定义PCP介导的力产生和对称破缺的机制， 集体细胞运动具体目标2将阐明差异细胞粘附模式如何促进 上皮运动性和防止细胞混合以划分集体上皮运动。具体 目的3将解释在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的相互作用如何产生大规模的集体 在器官形成过程中发生的运动，并揭示了结构性出生缺陷是如何产生的，当这些运动发生时， 流程就会出错

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.