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

细胞集体迁移是一个过程，在此过程中，多个细胞以协调的方式移动，受到群体内相邻细胞的影响，同时对环境线索做出反应。它发生在许多不同的环境中，而且已经表明，上皮片的集体运动在胚胎发育过程中发挥着重要作用。然而，虽然单个细胞迁移背后的分子和细胞机制已经被很好地理解，但我们才开始了解成组迁移的细胞如何协调它们的运动。最近，几项研究强调了集体细胞迁移的不同模式，都分享了保守的原则，如群体内的自组织和机械转导的重要作用。在Virginie Lecaudey团队的博士后工作期间，我建议使用初级后外侧线原基(PLLP)作为工作模型，以阐明引导细胞和跟随细胞协调其在群体中运动的机制。PLLP是沿着鱼的前后轴线形成感觉器官的一组上皮细胞。它是一个高度动态的系统，易于进行成像，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工具。勒考迪实验室已经证明了Motin蛋白Amotl2a在控制PLLP大小方面的意义。此外，Y2H的初步数据显示，Amotl2a与肿瘤抑制因子Merlin蛋白Nf2a和Nf2b以及细胞骨架蛋白Krt8(Krt8)之间存在强烈的相互作用。有趣的是，Merlin还通过与Motin蛋白相互作用并作为机械力化学转导来协调细胞的集体迁移。此外，角蛋白-钙粘连蛋白复合体也被认为是协调细胞运动的机械换能器。结合遗传、分子和细胞生物学、药理学治疗和创新的活体成像技术，我建议首先详细描述amotl2a突变体中PLLP细胞的迁移。然后，我将研究Merlin的定位以及Merlin和Amotl2a在细胞迁移过程中如何相互影响。我还将探索Amotl2a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著相似性，以及已知的机械转导在这两个过程中的重要性，我的结果应该为癌症生物医学研究提供新的感兴趣的机制。

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.