Supracellular synchronization of actomyosin contractility during collective neural crest cell durotaxis
Developmental Biology
Final Report Abstract
Collective cell migration is a highly coordinated process during embryonic development, tissue regeneration and metastasis formation, where groups of cells move in response to a migration-stimulating guidance cue. Several cancers, including breast and prostate cancer, collectively invade their target tissues. To gain invasiveness, many cell types lose their epithelial characteristics and acquire a mesenchymal identity that goes along with increased migratory properties. However, collective migration of mesenchymal cells has been largely overlooked, and most studies focused on spontaneously migrating epithelial cells cultured in vitro. To comprehend the cellular dynamics during collective mesenchymal cell migration, the host lab focusses on the neural crest (NC), an invasive mesenchymal cell population whose migratory behaviour resembles features of cancer invasion. NC cells migrate collectively throughout the embryo to differentiate into a variety of cell types, and the directionality of these cells has to be precisely controlled via different guidance cues. While it is well established that gradients of chemoattractive factors guide NC cell directionality in vivo, such chemogradients only provide short-range guidance. Mechanical guidance cues, like the topography and rigidity of the cell substrate, can provide guidance over longer distances and are therefore in the focus of current research. It was demonstrated by the host lab that durotaxis, the process of cells moving along a stiffness gradient, emerges in vivo during collective NC migration. Of note, NC cells migrate more effectively as a cluster than as single cells, indicating that cell-cell interactions are cooperative and improve coordination. Therefore, the host lab has proposed that a cluster of cells behaves as a ‘supracellular’ entity. Similar to single cell migration, supracellular durotaxis is dependent on a polarised organisation of the cytoskeleton, with protrusions at the leading edge and myosin II-based contractions at the rear of the cluster. Such supracellular behaviour requires extraordinary levels of intercellular communication, coordination, and synchronization. However, how this is achieved on the mechanistic and molecular scale, especially during durotaxis, is not understood. In the proposed project, we sought to decipher such processes, using Xenopus embryos and NC cell explants as model systems. We focussed on three main aspects. First, we aimed to investigate synergistic force-generation of nonmuscle myosin II (NM II) paralogs during collective NC durotaxis. Previous research has shown that such synergy can explain morphogenesis of single cells during migration, and we hypothesized that similar concepts could be transferred to collectively migrating clusters of NC cells. Second, we sought to investigate how individual NC cells communicate to each other, by focussing on gap junctions, tunnel-like cell-cell junctions that allow intercellular communication via propagation of second messengers like calcium ions. To this end, the third aspect was to investigate the propagation of calcium ions in the NC cluster, a known activator of NM II paralogs. We hypothesised that calcium ions might be propagated in a wave-like fashion through the NC cluster via gap junctions, ultimately allowing synchronized and synergistic contractions.
Publications
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Actomyosin forces in cell migration: Moving beyond cell body retraction. BioEssays, 46(10).
Weißenbruch, Kai & Mayor, Roberto
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Frictiotaxis underlies focal adhesion-independent durotaxis. Nature Communications, 16(1).
Shellard, Adam; Weißenbruch, Kai; Hampshire, Peter A. E.; Stillman, Namid R.; Dix, Christina L.; Thorogate, Richard; Imbert, Albane; Charras, Guillaume; Alert, Ricard & Mayor, Roberto
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Neural Crest Migration Orchestrated by Molecular and Mechanical Signals. Annual Review of Cell and Developmental Biology, 41(1), 159-185.
Weißenbruch, Kai & Mayor, Roberto
