Mechanical forces and their molecular control during epithelial folding in Drosophila

果蝇上皮折叠过程中的机械力及其分子控制

• 批准号: 428986026
• 负责人: Professor Dr. Christian Dahmann
• 金额: --
• 依托单位: Professur für Systembiologie und Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/428986026?language=en
• 关键词: Mechanical; forces; their; molecular; control

How form is generated is one of the big open questions in Developmental Biology. Embryos take shape by generating mechanical forces that deform epithelial sheets of cells covering the embryonic surface and inner organs. A fundamental shape change of epithelia, which takes place for example during gastrulation and the development of the eye, gut and brain, is folding. During folding, the quasi two-dimensional sheet of cells is transformed into a three-dimensional structure. A well-studied mechanism of epithelial folding is apical cell constriction. The contraction of an actomyosin network located at the apical side of cells generates mechanical forces that result in the narrowing of the apical side of cells. Coordinated apical constriction of neighboring cells results in epithelial folding. Our recent work has uncovered two additional novel mechanisms that are involved in epithelial folding. We showed by live imaging and quantitative image analysis that the formation of two neighboring folds in Drosophila wing discs, an important model system to study the development of epithelia, does not involve apical cell constriction, but rather the relaxation of the basal side of cells. In the first fold, basal relaxation correlates with a spatially defined decrease of extracellular matrix and decreased basal forces. In the second fold, basal relaxation is accompanied with a reduction in cell height that correlates with actin flows along the lateral interface between cells and increased lateral forces.The proposed work has three main aims: First, we will use optogenetics to alter force generation in cells to test whether decreased basal forces or increased lateral forces are necessary and sufficient for fold formation. Second, we will reveal how the reduction of basal force is confined to cells that form the first fold. Our preliminary data indicate that Wingless signal transduction specifies the position of this fold. We will combine force measurements with molecular genetics to test whether and how Wingless signal transduction controls basal forces. Third, we will combine live imaging with genetic analysis to decipher how actin flows are generated at the lateral side of cells and how they contribute to lateral forces. We expect that the proposed work will uncover novel principles by which mechanical forces are generated and molecularly controlled for tissues to take shape.

形态是如何产生的是发育生物学中的重大悬而未决的问题之一。胚胎通过产生机械力而形成，该机械力使覆盖胚胎表面和内部器官的细胞上皮片变形。上皮细胞的基本形状变化是折叠，这种变化发生在原肠胚形成以及眼睛、肠道和大脑发育期间。在折叠过程中，准二维细胞片转变为三维结构。上皮折叠的一个经过充分研究的机制是顶端细胞收缩。位于细胞顶端的肌动球蛋白网络的收缩产生机械力，导致细胞顶端变窄。邻近细胞的协调顶端收缩导致上皮折叠。我们最近的工作发现了另外两种与上皮折叠有关的新机制。我们通过实时成像和定量图像分析表明，果蝇翼盘（研究上皮细胞发育的重要模型系统）中两个相邻褶皱的形成并不涉及顶端细胞收缩，而是涉及细胞基侧的松弛。在第一折叠中，基础松弛与细胞外基质的空间限定减少和基础力降低相关。在第二次折叠中，基底松弛伴随着细胞高度的降低，这与肌动蛋白沿着细胞之间的横向界面流动和增加的侧向力相关。这项工作有三个主要目标：首先，我们将利用光遗传学来改变细胞中力的产生，以测试降低基底力或增加侧向力是否对于折叠形成是必要和充分的。其次，我们将揭示基础力的减少如何局限于形成第一折叠的细胞。我们的初步数据表明 Wingless 信号转导指定了该折叠的位置。我们将把力测量与分子遗传学结合起来，测试 Wingless 信号转导是否以及如何控制基础力。第三，我们将实时成像与遗传分析相结合，以破译肌动蛋白流是如何在细胞侧面产生的以及它们如何对横向力产生影响。我们期望所提出的工作将揭示产生机械力并通过分子控制组织成形的新原理。