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Collective cell migration is an essential feature both in embryonic development and cancer progression. The molecular mechanisms of these coordinated directional cell movements still need to be elucidated. The migration of cranial neural crest (CNC) cells during embryogenesis is an excellent model for collective cell migration in vivo. These highly motile and multipotent cells migrate directionally on defined routes throughout the embryo. Interestingly, local cell-cell interactions seem to be the key force for directionality. CNC cells can change their migration direction by a repulsive cell response called contact inhibition of locomotion (CIL). Cell protrusions collapse upon homotypic cell-cell contact and internal repolarization leads to formation of new protrusions toward cell-free regions. Wnt/PCP signaling was shown to mediate activation of small RhoGTPase RhoA and inhibition of cell protrusions at the contact side. However, the mechanism how a cell recognizes the contact is poorly understood. Here, we demonstrate that Xenopus cadherin-11 (Xcad-11) mediated cell-cell adhesion is necessary in CIL for directional and collective migration of CNC cells. Reduction of Xcad-11 adhesive function resulted in higher invasiveness of CNC due to loss of CIL. Additionally, transplantation analyses revealed that CNC migratory behaviour in vivo is non-directional and incomplete when Xcad-11 adhesive function is impaired. Blocking Wnt/PCP signaling led to similar results underlining the importance of Xcad-11 in the mechanism of CIL and directional migration of CNC.
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24392028 ???displayArticle.pmcLink???PMC3877381 ???displayArticle.link???PLoS One ???displayArticle.grants???[+]
Figure 2. Xcad-11 is required for directional CNC migration in vivo.CNC transplants. First column: Lateral view on transplanted GFP-labelled Xenopus CNC before migration at stage 19. Second column: Lateral view on transplanted GFP-labelled Xenopus CNC after migration at stage 26. Third column: Tracking analysis of six to seven cells by H2B-cherry labelled nuclei during CNC migration (stage 19-26). Anterior is to the left and dorsal to the top. (A) Wildtype grafts showed normal migration. (B) Grafts coinjected with Xcad-11-MO were unable to migrate into the pharyngeal pouches. (C, D) Overexpression by coinjection of dn-Xcad-11 and Dsh(DEP+), respectively, led to disorientated and not directional CNC migration. (E) Schematic illustration of the transplantation assay. Percentage of complete CNC migration given in (F) with n = number of transplanted embryos. Error bar shows standard error. (***) Significance to wildtype with p<0.005 after student’s T-Test. Scale bar, 200 µm.
Figure 3. Loss of Xcad-11 adhesive function increases CNC invasiveness in vitro.Confrontation assay. First column: Confronted explants at time point t=0. Second column: Confronted CNC explants at time point of highest invasion Δt. Third column: Morphology of CNC cells. Except for (A) wildtype vs. wildtype, yellow overlapping area increased strongly in (B) Xcad-11 morphant, (C) dn-Xcad-11 and (D) Dsh(DEP+) overexpressing CNC cells reflecting invasiveness of the tissues. Xcad-11 depleted cells displayed blebbing (yellow arrowheads in (B)) in contrast to protrusion formation of CNC cells in other approaches (white arrowheads in (A, C, D)). (E) Schematic illustration of the confrontation assay. Average Overlapping Index (OI) given in (F) with n = number of confrontations (wt: wildtype). Error bar shows standard error. (***) Significance to wildtype vs. wildtype with p<0.001 after student’s T-Test. Scale bar, 50 µm.
Figure 4. Xcad-11 mediates repulsive response in colliding in single CNC cells in vitro.Collision assay. First three columns: Single CNC cells before (t-Δ), during (t) and after (t+Δ) mutual contact with tracking. Fourth column: Relative velocity vectors with initial velocity vector (red, n = 10 collisions). (A) Only wildtype CNC cells showed change of direction. (B) Xcad-11-MO treated cells show random distribution. (C) dn-Xcad-11 and (D) Dsh(DEP+) overexpressing CNC cells displayed reduced repulsive response. Scale bar, 50 µm.
Figure 1. Depletion of Xcad-11 adhesive function blocks CNC migration in vivo.Lateral view of Xenopus CNC at stage 26, analysed by whole-mount ISH for the specific CNC marker AP-2α. Left column: Injected side (IS). Right column: Non-injected side (NIS). (A) Wildtype CNC cells migrated in defined streams into the pharyngeal pouches. (B) Xcad-11-MO injected embryos show AP-2α staining only at the dorsal part of the embryo, indicating incomplete CNC migration compared to NIS. (C) Overexpression of dn-Xcad-11 and (D) Dsh(DEP+) both showed incomplete and fused CNC hyoidal and branchial migration streams. Percentage of complete CNC migration given in (E) with n = number of embryos. Error bar shows standard error. (***) Significance to wildtype with p<0.005 after student’s T-Test. Scale bar, 250 µm.
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