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

• Applicant: Dr. Alicia Lardennois
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450757067

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.

• DFG Programme: WBP Position