Maik Bischoff (University of North Carolina at Chapel Hill)

Semaphorin-Plexin Antagonism Orchestrates Collective Cell Migration in vivo

Host: Stefan Luschnig

Cells migrate collectively to form tissues and organs during morphogenesis, a behavior adopted by many metastatic cancer cells. Collective cell migration requires directed, coherent movement of cell groups. We previously developed a new model to explore underlying mechanisms: Drosophila muscle cell precursors migrating to ensheath the testis. This system allows high-resolution 4D live-cell imaging of collectively migrating cells in intact tissue. These cells don’t migrate as an epithelial sheet but as a group of highly dynamic - yet N-Cadherin connected - mesenchymal cells. Myotubes self-regulate their migratory behavior in a cell-cell contact-dependent manner. To find potential regulators, we performed a large-scale RNAi screen with candidates derived from tissue-specific RNAseq. This screen revealed that PlexinA and its membrane-bound ligand Semaphorin1B are required for normal migration. Semaphorin/Plexin signaling is well-known in axon guidance, where Semaphorins secreted by the environment are sensed by Plexin-expressing axons. In contrast, within our tissue Sema1B and PlexA both act within the migrating cells. In wild type, migrating cells adopt a flattened mesenchymal morphology, allowing them to easily move in the confined space between the germline and overlying pigment cells. After genetic plexA pertubation, cells are more densely packed and less flattened and form large gaps in the migrating sheet. Knockdown cells have reduced cell-matrix adhesions adjacent to cell-cell contacts that are remodeled. Interdigitating filopodial N-Cadherin-mediated contacts are replaced with a more linear cell-cell interface, more reminiscent of epithelial junctions. Our data suggest that PlexA is employed by myotubes to self-regulate migration and allow gap closure by modulating the adhesive and protrusive properties of cell-cell edges. This exchange of information of neighbors is important to keep the mesenchymal cell sheet flat, and therefore may facilitate migration under confinement. Genetic interaction experiments suggested that Semaphorin1B plays an unexpected role in fine-tuning PlexA activity by acting as an antagonist, consistent with recent structural studies. Surprisingly, knockdown of sema1b also leads to gap formation, albeit by an opposing mechanism that leads to a reduction in cell-cell adhesion and more single-cell behaviour.

Detailed information