Molecular control of tissue morphogenesis

描述（由申请人提供）：产生组织结构的组织原理对器官系统的形成和功能至关重要。发育生物学的一个主要挑战是了解组织结构如何在细胞和分子水平上产生。细胞嵌入是一个保守的形态发生过程，涉及数百个细胞，产生胚胎形式的惊人特性之一-体轴。这个过程是由极化细胞行为介导的，但产生这些行为的机制在很大程度上是未知的。该提案的目标是了解插入细胞如何建立极性，定义将这些极性转化为定向细胞行为的分子组分，并表征将这些细胞行为与组织结构转化联系起来的细胞相互作用。我们发现，在果蝇胚胎中的闰细胞显示的粘附连接和肌动蛋白肌球蛋白电缆，可以直接影响细胞运动的不对称分布。为了理解极性的这些性质是如何建立和协调的，我们将定义在嵌入细胞中形成的最早的不对称性。我们推测，第一个蛋白质定位可能会直接组织其他亚细胞区室。为了验证这一假设，我们将分析特定成分缺陷突变体的极性。这些研究将提供有关在嵌入细胞中产生细胞结构的分子机制的信息。在正向遗传筛选中，我们确定了果蝇中轴伸长所需的新型连接蛋白和运输蛋白。我们预测，这些蛋白质管理的极化定位或活动的连接蛋白，介导细胞相互作用的重要轴伸长，预测我们将测试通过分析突变体胚胎的连接极性。与这种可能性相一致的是，果蝇生殖带中插入细胞的行为是由细胞之间的局部细胞相互作用指导的，尽管这些相互作用的性质还没有很好地定义。我们将结合联合收割机的时间推移共聚焦成像与统计物理学和计算机科学的定量方法来研究局部细胞的相互作用，产生组织伸长过程中细胞行为的紧急模式。了解正常组织发育过程中细胞行为的机制，可能有助于了解影响器官形成的发育性疾病的病因。细胞嵌入对于神经管闭合至关重要，而这一过程的中断是常见出生缺陷的原因。此外，了解正常发育过程中细胞接触的动态调节可能有助于了解肿瘤细胞转移的过程，其中连接蛋白的失调是上皮肿瘤进展的关键步骤。

DESCRIPTION (provided by applicant): The organizing principles that generate tissue structure are critical to the formation and function of organ systems. A major challenge in developmental biology is to understand how tissue structure is generated on a cellular and molecular level. Cell intercalation is a conserved morphogenetic process involving hundreds of cells that generates one of the striking properties of embryonic form - the body axis. This process is mediated by polarized cell behaviors, but the mechanisms that generate these behaviors are largely unknown. The goal of this proposal is to understand how intercalating cells establish polarity, define the molecular components that translate these polarities into directed cell behavior, and characterize the cell interactions that link these cell behaviors to a transformation in tissue structure. We found that intercalating cells in the Drosophila embryo display an asymmetric distribution of adherens junctions and actin-myosin cables that could directly influence cell movement. To understand how these properties of polarity are established and coordinated, we will define the earliest asymmetries that form in intercalating cells. We hypothesize that the first proteins to localize may direct the organization of other subcellular compartments. To test this hypothesis, we will analyze polarity in mutants defective for specific components. These studies will provide information about the molecular mechanisms that generate cytoarchitecture in intercalating cells. In a forward genetic screen, we identified novel junctional and trafficking proteins that are required for axis elongation in Drosophila. We predict that these proteins govern the polarized localization or activity of junctional proteins that mediate cell interactions important for axis elongation, a prediction we will test by analyzing junctional polarity in mutant embryos. Consistent with this possibility, the behavior of intercalating cells in the Drosophila germband is guided by local cell interactions between cells, although the nature of these interactions is not well-defined. We will combine time-lapse confocal imaging with quantitative approaches from statistical physics and computer science to investigate local cell interactions that generate emergent patterns of cell behavior during tissue elongation. An understanding of the mechanisms that govern cell behavior during normal tissue development may provide insight into the etiology of developmental diseases that affect organ formation. Cell intercalation is essential for neural tube closure, and disruption of this process is responsible for common birth defects. In addition, insight into the dynamic regulation of cell contacts during normal development may shed light on processes of tumor cell metastasis, where misregulation of junctional proteins is a critical step in the progression of epithelial tumors.