Supracellular synchronization of actomyosin contractility during collective neural crest cell durotaxis

• Applicant: Dr. Kai Weissenbruch
• Subject Area: Cell Biology ; Developmental Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513518868

Collective cell migration is a highly coordinated process during development, regeneration and metastasis formation. Neural crest cells, an invasive mesenchymal cell population, collectively migrate not only in response to chemical factors but also along stiffness gradients in the underlying substratum, a process called durotaxis. Collective durotaxis requires extraordinary levels of mechanosensing, symmetry breaking, intercellular communication and synchronized actomyosin contraction, to coordinate a directional supracellular movement. However, how collectively migrating neural crest cells communicate, in order to synchronize their protrusive and force-generating machineries across several cell borders during durotaxis, is still not understood. Using Xenopus embryos as a model system, we seek to decipher these processes by investigating the synergy of force-generating nonmuscle myosin II paralogs, intercellular communication via gap junctions, and calcium propagation, in vitro and in vivo. In my PhD research, I showed that in vitro, the intrinsic features of the nonmuscle myosin II paralogs A and B complement each other during force generation and morphogenesis of single cells. While paralog A provides rapid tugging forces, necessary to initiate the contractile machinery throughout the cell body, paralog B gradually stabilizes pre-initiated contractions in subcellular regions to autonomously generate a polarized actomyosin network across the cell body. Although this concept can explain the morphogenesis of individual migrating cells, in this project I hypothesize that similar principles can be applied to explain collective durotaxis in vivo of multicellular neural crest cell cluster. To investigate the pathway that mediates synchronized actomyosin contraction across multiple adjacent cells, we will focus on intercellular communication via gap junctions, transmembrane channels that connect the cytoplasm of adjacent cells, allowing exchange of signalling molecules and ions. Preliminary data from the host lab suggest that gap junctions are involved in collective neural crest migration. We will unravel if gap junctional intercellular communication mediates the synchronization of the contractile machinery and how it influences the generation of a polarized actomyosin network, considering the distinct nonmuscle myosin II paralogs. In order to identify possible signals that could be propagated via gap junctions and influence the actomyosin cytoskeleton, we will focus on calcium ions and IP3-mediated calcium release from internal stores. Calcium is a well-known actomyosin stimulator and preliminary data from the host lab suggest that IP3 is involved in calcium signalling during collective neural crest migration. We expect that this multidisciplinary project will provide answers to a central yet unresolved question: how individual cells are coordinated during collective cell migration.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Roberto Mayor, Ph.D.