Investigating the mechanisms by which cells coordinate their movements within a migrating cell group using the zebrafish lateral line

使用斑马鱼侧线研究细胞在迁移细胞群内协调运动的机制

• 批准号: 450757067
• 负责人: Dr. Alicia Lardennois
• 金额: --
• 依托单位: Institut für Zellbiologie und Neurowissenschaft
• 依托单位国家: 德国
• 项目类别: WBP Position
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/450757067?language=en
• 关键词: Investigating; mechanisms; cells; coordinate; their

Collective cell migration is a process during which multiple cells move in a coordinated manner influenced by their neighbours within the group and at the same time reacting to environmental cues. It occurs in many different contexts and it has been shown that collective movements of epithelial sheets play a fundamental role during the development of embryos. However, while the molecular and cellular mechanisms underlying the migration of individual cells are well understood, we only start to grasp how cells migrating in groups coordinate their movements. Recently, several studies highlighted different models of collective cell migration, all sharing conserved principles such as self-organization within the group and the important role of mechanotransduction. During my post-doctoral work in Virginie Lecaudey’ team, I propose to use the primary posterior lateral line primordium (pLLP) as a working model to elucidate the mechanisms by which leading and trailing cells coordinate their movements within the group. The pLLP is a migrating group of epithelial cells forming sensory organs along the antero-posterior axis of the fish. It is a highly dynamic system and it is easily accessible for imaging, making it ideal to track protein localization and cell shape changes during tissue morphogenesis. The Lecaudey lab has already proved the implication of the Motin Protein Amotl2a in controlling the size of the pLLP. In addition, preliminary Y2H data show a strong interaction between Amotl2a and the tumor suppressor Merlin proteins Nf2a and Nf2b and the cytoskeletal protein Keratin 8 (Krt8). Interestingly, Merlin is also known to coordinate collective migration of cells, by interacting with Motin protein and acting as a mechanochemical transducer. Moreover, a Keratin-Cadherin complex has also been proposed to act as a mechanotransducer to coordinate cell movement. Combining genetic, molecular and cellular biology, pharmacological treatments, and innovative live imaging techniques, I propose to first characterize in detail the migration of the pLLP cells in amotl2a mutants. Then, I will investigate Merlin’s localization and how Merlin and Amotl2a influence each other during cell migration. I will also explore the physical/genetic interaction between Amotl2a and the keratin-based cytoskeleton. Given the significant similarities between the lateral line morphogenesis and tumor metastasis, as well as the known importance of mechanotransduction in both processes, my results should provide new mechanisms of interest for cancer biomedical research.

集体细胞迁移是一个过程，在此过程中，多个细胞以协调的方式移动，受到组内相邻细胞的影响，同时对环境线索做出反应。它发生在许多不同的情况下，它已被证明，集体运动的上皮片在胚胎的发育过程中发挥了重要作用。然而，虽然单个细胞迁移的分子和细胞机制已经很好地理解，但我们只是开始掌握细胞如何在群体中迁移协调它们的运动。最近，几项研究强调了集体细胞迁移的不同模型，所有这些模型都具有保守的原则，例如组内的自组织和机械转导的重要作用。在我的博士后工作中，我建议使用初级后侧线原基（pLLP）作为一个工作模型，以阐明领导和尾随细胞协调其在组内运动的机制。pLLP是一组上皮细胞，沿鱼的前后轴沿着形成感觉器官。它是一个高度动态的系统，易于成像，使其成为跟踪组织形态发生过程中蛋白质定位和细胞形状变化的理想选择。Lecaudey实验室已经证明了运动蛋白Amotl 2a在控制pLLP大小方面的意义。此外，初步的Y2 H数据显示Amotl 2a与肿瘤抑制因子Merlin蛋白Nf 2a和Nf 2b以及细胞骨架蛋白角蛋白8（Krt 8）之间的强相互作用。有趣的是，Merlin还已知通过与Motin蛋白相互作用并充当机械化学换能器来协调细胞的集体迁移。此外，角蛋白-钙粘蛋白复合物也被提出作为机械传感器来协调细胞运动。结合遗传，分子和细胞生物学，药理学治疗，和创新的现场成像技术，我建议首先详细描述amotl 2a突变体中pLLP细胞的迁移。然后，我将研究梅林的定位和梅林和Amotl 2a如何影响对方在细胞迁移。我还将探索Amotl 2a和基于角蛋白的细胞骨架之间的物理/遗传相互作用。鉴于侧线形态发生和肿瘤转移之间的显着相似性，以及已知的mechanotransduction在这两个过程中的重要性，我的研究结果应该提供新的机制感兴趣的癌症生物医学研究。