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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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???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 studentâs 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 Ît. 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 studentâs 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-Î), during (t) and after (t+Î) 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.
Abercrombie,
Contact inhibition and malignancy.
1979, Pubmed
Abercrombie,
Contact inhibition and malignancy.
1979,
Pubmed
Abercrombie,
Contact inhibition in tissue culture.
1970,
Pubmed
,
Xenbase
ABERCROMBIE,
The surface properties of cancer cells: a review.
1962,
Pubmed
Alfandari,
Mechanism of Xenopus cranial neural crest cell migration.
2010,
Pubmed
,
Xenbase
Astin,
Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells.
2010,
Pubmed
Backer,
Trio controls the mature organization of neuronal clusters in the hindbrain.
2007,
Pubmed
Becker,
Giving the right tug for migration: cadherins in tissue movements.
2012,
Pubmed
Bellanger,
The two guanine nucleotide exchange factor domains of Trio link the Rac1 and the RhoA pathways in vivo.
1998,
Pubmed
Boggon,
C-cadherin ectodomain structure and implications for cell adhesion mechanisms.
2002,
Pubmed
,
Xenbase
Borchers,
Xenopus cadherin-11 restrains cranial neural crest migration and influences neural crest specification.
2001,
Pubmed
,
Xenbase
Bussemakers,
Complex cadherin expression in human prostate cancer cells.
2000,
Pubmed
Carmona-Fontaine,
Contact inhibition of locomotion in vivo controls neural crest directional migration.
2008,
Pubmed
,
Xenbase
Carmona-Fontaine,
Complement fragment C3a controls mutual cell attraction during collective cell migration.
2011,
Pubmed
,
Xenbase
Chang,
Cadherin-11 regulates fibroblast inflammation.
2011,
Pubmed
Chu,
Cadherin-11 promotes the metastasis of prostate cancer cells to bone.
2008,
Pubmed
De Calisto,
Essential role of non-canonical Wnt signalling in neural crest migration.
2005,
Pubmed
,
Xenbase
Hadeball,
Xenopus cadherin-11 (Xcadherin-11) expression requires the Wg/Wnt signal.
1998,
Pubmed
,
Xenbase
Harland,
In situ hybridization: an improved whole-mount method for Xenopus embryos.
1991,
Pubmed
,
Xenbase
Jaffe,
Rho GTPases: biochemistry and biology.
2005,
Pubmed
Kashef,
Cadherin-11 regulates protrusive activity in Xenopus cranial neural crest cells upstream of Trio and the small GTPases.
2009,
Pubmed
,
Xenbase
LaBonne,
Molecular mechanisms of neural crest formation.
1999,
Pubmed
,
Xenbase
Lee,
Cadherin-11 in synovial lining formation and pathology in arthritis.
2007,
Pubmed
Mayor,
Keeping in touch with contact inhibition of locomotion.
2010,
Pubmed
Mayor,
The neural crest.
2013,
Pubmed
,
Xenbase
McCusker,
Extracellular cleavage of cadherin-11 by ADAM metalloproteases is essential for Xenopus cranial neural crest cell migration.
2009,
Pubmed
,
Xenbase
Moore,
Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion.
2013,
Pubmed
,
Xenbase
Patel,
Type II cadherin ectodomain structures: implications for classical cadherin specificity.
2006,
Pubmed
,
Xenbase
Pishvaian,
Cadherin-11 is expressed in invasive breast cancer cell lines.
1999,
Pubmed
Sadaghiani,
Neural crest development in the Xenopus laevis embryo, studied by interspecific transplantation and scanning electron microscopy.
1987,
Pubmed
,
Xenbase
Sauka-Spengler,
A gene regulatory network orchestrates neural crest formation.
2008,
Pubmed
Shoval,
Antagonistic activities of Rho and Rac GTPases underlie the transition from neural crest delamination to migration.
2012,
Pubmed
Steventon,
Early neural crest induction requires an initial inhibition of Wnt signals.
2012,
Pubmed
,
Xenbase
Theveneau,
Chase-and-run between adjacent cell populations promotes directional collective migration.
2013,
Pubmed
Theveneau,
Collective chemotaxis requires contact-dependent cell polarity.
2010,
Pubmed
,
Xenbase
Tomita,
Cadherin switching in human prostate cancer progression.
2000,
Pubmed
Vallin,
Xenopus cadherin-11 is expressed in different populations of migrating neural crest cells.
1998,
Pubmed
,
Xenbase
van Rijssel,
The N-terminal DH-PH domain of Trio induces cell spreading and migration by regulating lamellipodia dynamics in a Rac1-dependent fashion.
2012,
Pubmed
Watanabe,
Cadherin-mediated intercellular adhesion and signaling cascades involving small GTPases.
2009,
Pubmed
