Mechanisms of epithelial migration and basement membrane assembly

项目摘要/摘要 上皮细胞的集体迁移在形态发生、肠道周转、伤口修复、 和转移。上皮细胞使用与单个细胞相同的迁移机制。对于上皮片而言， 然而，迁移时，这台机器必须在整个组织平面上全局对齐。确定这是如何 实现组织水平的极化是集体迁移领域的中心目标。我们研究一种旋转形式 指当组织被限制在圆形或球状几何形状时发生的上皮迁移。旋转 迁移与其他上皮迁移在两个方面不同。首先，外部线索，如空白空间或化疗- 战术信号不能用于指导组织极化。相反，单元必须完全依赖于本地单元-单元 达到这种状态的相互作用。细胞如何自组织以进行旋转迁移尚不清楚。第二，有 没有组织的净运动，这就提出了为什么会发生这些迁移的问题。旋转促进了 基底膜细胞外基质的组装，排列在组织的基底面；它甚至可以 创造高度结构化的基底膜，引导器官形态发生。然而，如何旋转 对基底膜组装的影响知之甚少。值得注意的是，最近的研究表明，上皮细胞 旋转可能有助于人体器官的发育，因为乳腺器官的球形肺泡像 它们是在连接到中央管网的情况下形成的。 我的NIGMS资助的研究有两个目标：(1)定义允许上皮细胞的局部细胞-细胞相互作用 旋转迁移的自组织，以及(2)确定旋转如何构造基底膜。 为此，我们正在研究发生在果蝇毛囊上皮中的旋转迁移。在……里面 近年来，我们使用这个模型来提供对局部细胞-细胞相互作用的第一次洞察，这种相互作用使 通过识别一个新的平面信号系统来调节这一过程，从而促进上皮细胞的旋转迁移。我们 还表明，旋转与新的蛋白质分泌一起工作，在基底膜中产生纤维， 控制组织形状。通过Mira计划，我们将更深入地挖掘这两种机制。我们将决定 平面信号系统如何允许卵泡细胞打破对称性并启动迁移，以及如何 信号在分子水平上起作用--无论是蛋白质之间相互作用的方式，还是与 迁徙机械。我们还将探索两种机制，即通过旋转 迁移可能会影响基底膜的组装。这项工作将揭示新的指导原则 组织层面的秩序如何从局部的细胞-细胞相互作用中产生。此外，由于基底膜 是大多数器官的中心，其组件中的缺陷包括肌营养不良、肾病、皮肤 水泡和中风，我们对这个鲜为人知的过程所了解的任何事情都将产生广泛的影响。

PROJECT SUMMARY / ABSTRACT Collective migration of epithelial cells plays central roles in morphogenesis, intestinal turnover, wound repair, and metastasis. Epithelial cells use the same migration machinery as individual cells. For an epithelial sheet to migrate, however, this machinery must become globally aligned across the tissue plane. Determining how this tissue-level polarization is achieved is a central goal of the collective migration field. We study a rotational form of epithelial migration that occurs when the tissue is confined to a circular or spherical geometry. Rotational migrations differ from other epithelial migrations in two ways. First, external cues like empty space or chemo- tactic signals are not available to guide tissue polarization. Instead, the cells must rely solely on local cell-cell interactions to achieve this state. How cells self-organize for rotational migration is unknown. Second, there is no net tissue movement, which raises the question of why these migrations occur. Rotation promotes the assembly of the basement membrane extracellular matrix that lines the tissue’s basal surface; it can even create highly structured basement membranes that direct organ morphogenesis. However, how rotation impacts basement membrane assembly is poorly understood. Notably, recent work has shown that epithelial rotation may contribute to human organ development, as the spherical alveoli of mammary organoids rotate as they form despite being connected to a central ductwork. My NIGMS-funded research has two goals: (1) to define the local cell-cell interactions that allow epithelial cells self-organize for rotational migration, and (2) to determine how rotation structures the basement membrane. To this end, we are studying a rotational migration that occurs in the follicular epithelium of the Drosophila. In recent years, we used this model to provide the first insight into the local cell-cell interactions that polarize an epithelium for rotational migration by identifying a novel planar signaling system that mediates this process. We also showed that rotation works with new protein secretion to create fibrils in the basement membrane that control tissue shape. Through the MIRA program, we will dig deeper into both mechanisms. We will determine how the planar signaling system allows the follicle cells to break symmetry and initiate migration and how the signaling works at molecular level - both in terms of how the proteins interact with one another and with the migration machinery. We will also explore two mechanisms by which mechanical forces imparted by rotational migration are likely to influence basement membrane assembly. This work will reveal new guiding principles for how tissue-level order can emerge from local cell-cell interactions. Moreover, because basement membranes are central to most organs and defects in their assembly underly muscular dystrophy, nephropathy, skin blistering, and stroke, anything we learn about this poorly understood process will have broad impact.