Intercellular junctions as force integrating anchors during epithelial cell shape transitions

上皮组织覆盖着我们全身的器官表面，发挥着保护、分泌和吸收等关键功能。虽然作用于黏附连接平面的形态发生机制已受到广泛关注，但对于柱状-立方体-鳞状形状谱中3D上皮细胞形状的多样性如何产生却知之甚少。在SPP1782的第一个资助阶段专注于立方-柱状形状的转变之后，我们现在建议专门探索促进鳞状细胞形状形成的细胞生物学、遗传学和生物力学机制。我们将探讨在果蝇毛囊上皮细胞扁平化过程中，细胞内力和细胞外力在E-钙粘附素依赖的细胞-细胞黏附水平上整合以指导集体细胞行为的假说。丰富的细胞形态、简单的结构和易于显微处理的特性使毛囊细胞上皮成为本研究的理想体内模型系统。我们建议将经典的定量细胞生物学和遗传学研究与组织内生物力学参数的分析结合起来。我们将与几个SPP项目联合起来，揭示E-钙粘蛋白在调节上皮细胞形状中保守的机械敏感机制。我们拟议的工作具体符合SPP的目标，即了解细胞间连接如何感知机械力，机械信号如何指导细胞行为，从而旨在为上皮形态发生的一个鲜为人知但意义深远的基本方面提供新的见解。

Epithelial tissues cover organ surfaces throughout our body and fulfil crucial functions such as protection, secretion and absorption. While morphogenetic mechanisms acting in the plane of adherens junctions have received much attention, little is known about how the diversity of 3D epithelial cell shapes within the columnar-cuboidal-squamous shape spectrum arises. Having focused on cuboidal-columnar shape transition in the first funding phase of the SPP1782, we now propose to specifically explore cell biological, genetic and biomechanical mechanisms that promote morphogenesis of squamous cell shapes. We will investigate the hypothesis that cell-intrinsic and cell-extrinsic forces are being integrated at the level of E-cadherin dependent cell-cell adhesion to guide collective cell behaviors during flattening of Drosophila follicle epithelial cells. The richness in cell shapes, a simple architecture and the easy microscopic tractability makes the follicle cell epithelium an ideal in vivo model system for this study. We propose to merge classical quantitative cell biological and genetic studies with the analysis of biomechanical parameters within the tissue. We will join forces with several SPP projects, to uncover conserved mechanosensitive mechanisms of E-cadherin function in the regulation of epithelial cell shape. Our proposed work specifically aligns with the goals of the SPP to understand how mechanical forces are sensed at intercellular junctions, how mechanical signals guide cell behaviour, and thereby aims to provide novel insights into a little understood, but profoundly fundamental aspect of epithelial morphogenesis.