Regulation of Cohesive Cell Migration in Drosophila Embryogenesis

描述（由申请人提供）：细胞迁移对胚胎发育、伤口愈合过程和肿瘤转移等病理状况至关重要。对细胞定向迁移的机制的理解将为组织和器官的形成提供基本的见解，并将帮助我们理解这些机制在伤口愈合过程中是如何应用的，以及在癌症进展过程中是如何出错的。我们开发了一个简单的模型系统来研究果蝇的内聚细胞迁移。在果蝇中，将反向和正向遗传方法结合起来，实时研究完整生物体中的细胞迁移，使我们能够识别参与这一过程的基因，并了解它们在细胞迁移中所起的确切作用。由于人类和无脊椎生物之间的信号网络是守恒的，这些研究的结果可以应用于人类细胞的迁移。利用培养的哺乳动物细胞进行的研究揭示了单细胞在培养物中迁移的机制。我们目前面临的挑战是了解这些机制是否也适用于内聚细胞迁移，以及内聚细胞迁移与单细胞迁移有何不同。在这里，我们集中在两个悬而未决的问题有关内聚细胞迁移；1)迁移上皮细胞对基质的粘附如何与细胞间的细胞间粘附协调；2)在迁移簇内如何产生极性以进行净定向迁移。我们的第一个具体目标是验证这样一个假设，即整合素介导的迁移上皮细胞和它们迁移的中表皮细胞之间的粘附通过激活小GTPase Rac来引导上皮细胞的初始迁移路径。我们的第二个目的是验证Rac介导上皮向前前部的迁移和后部的收缩的假设。在我们的第三和第四个目标中，我们将鉴定和描述在正向遗传学筛选中鉴定的两个新基因，以确定它们在内聚细胞迁移过程中整合素介导的粘附中的作用。细胞迁移对胚胎发育、伤口愈合和肿瘤转移至关重要。我们建议研究细胞如何在胚胎中凝聚迁移，以便我们可以应用我们的知识来设计治疗方法，以加速或延迟伤口愈合，防止癌细胞的迁移和入侵。

DESCRIPTION (provided by applicant): Cell migration is essential for embryonic development, wound healing processes and pathological conditions such as tumor metastasis. An understanding of the mechanism by which cells migrate cohesively in a directed manner will provide fundamental insights into the formation of tissues and organs and will help us understand how these mechanisms are applied during wound healing and go awry during cancer progression. We have developed a simple model system to study cohesive cell migration using the fruit fly Drosophila. In Drosophila, the combination of reverse and forward genetic approaches with the ability to study cell migration in an intact organism in real time allows us to identify genes involved in this process and understand the precise roles they play in cell migration. Due to the conservation of signaling networks between humans and invertebrate organisms, results of these studies can be applied to migration of human cells. Studies using cultured mammalian cells have revealed the mechanism by which single cells migrate in culture. Our current challenge is to understand whether such mechanisms also apply to cohesive cell migration and how cohesive cell migration differs from single cell migration. Here we focus on two unanswered questions concerning cohesive cell migration; 1) how adhesion of migrating epithelial cells to the substratum is coordinated with cell-cell adhesion between cells and 2) how polarity is generated within the migrating cluster for net directed migration. Our first specific aim is to test the hypothesis that integrin-mediated adhesion between the migrating epithelial cells and the mesodermal cells upon which they migrate guide the initial migratory path of the epithelia by activating the small GTPase Rac. Our second aim is to test the hypothesis that Rac mediates migration of the advancing front and contraction of the rear of the epithelium. In our third and fourth aims we will identify and characterize two novel genes identified in a forward genetics screen for their roles in integrin-mediated adhesion during cohesive cell migration. Cell migration is essential for embryonic development, wound healing and tumor metastasis. We propose to study how cells migrate cohesively in the embryo so that we can apply our knowledge to design therapies to expedite or delay wound healing and prevent migration and invasion of cancer cells.