Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces

Abstract

SummaryContact inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell contact, and it contributes to malignant invasion and developmental migration. Various cell types exhibit CIL, whereas others remain in contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo.

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…The main functional difference between epithelial and mesenchymal AJs is their stability: epithelial junctions tend to be more stable (in the range of hours to days), whereas mesenchymal junctions are transient (minutes to hours) (Scarpa et al 2015). The stability of AJs is controlled by several mechanisms, including endocytosis and cytoskeletal regulation.…”

“…A BMP4-Wnt1 signaling pathway activates a set of transcription factors, including Snail1/2, Sox5/9/10, Foxd3 and Ets1, that modify the expression of cell -cell and cell -matrix adhesion molecules (Sauka-Spengler and Bronner-Fraser 2008;Theveneau and Mayor 2012c). Thus, although neural crest shows all the hallmarks of mesenchymal cells, they obviously form transient AJs (Scarpa et al 2015). The endocytosis of N-cadherin at the AJs is essential for neural crest migration in vivo, as it confers sufficient fluidity on the cell cluster for it to migrate under physical constrains (Kuriyama et al 2014).…”

“…1E) (Scarpa et al 2015). Examples are the migration of neural crest cells in developing embryos, neuronal/astrocyte networks (Scarpa et al 2015), glioma cells retaining filamentous cell -cell interactions while moving through complex brain parenchyma (Osswald et al 2015), and mesenchymal tumor cells moving through confining tissue (Ilina et al 2011;Haeger et al 2014). Collectively, moving loose networks are mediated by complex morphological junctions mediated by N-cadherin for cell-cell adhesion and additional receptors mediating repulsive signals, including Ephrin/Eph receptors (Theveneau and Mayor 2011).…”

“…A more flexible type of collective migration, used by neural crest and other mesenchymal cells, as they move in a coordinated manner as loosely cohesive group in a cell-type and context-dependent way, with a variable tendency to individualize (Fig. 1E) (Scarpa et al 2015). Examples are the migration of neural crest cells in developing embryos, neuronal/astrocyte networks (Scarpa et al 2015), glioma cells retaining filamentous cell -cell interactions while moving through complex brain parenchyma (Osswald et al 2015), and mesenchymal tumor cells moving through confining tissue (Ilina et al 2011;Haeger et al 2014).…”

Ca2+/H+exchange by acidic organelles regulates cell migration in vivo

“…To determine the subcellular localization of animal CAX, we performed ex vivo experiments with neural crest explants (Scarpa et al, 2015). Confocal microscopy of explants expressing GFP-CAX revealed a vesicular pattern of staining (Fig.…”