Cadherin-11 Mediates Contact Inhibition of Locomotion during Xenopus Neural Crest Cell Migration

Abstract

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.

Cadherins function during the collective cell migration of Xenopus Cranial Neural Crest cells: revisiting the role of E-cadherin

“…In Xenopus, CIL requires the activation of the Wnt-Planar Cell Polarity (PCP) pathway. This activation requires N-cadherin and cadherin-11 and modulates the activity of small GTPases RhoA and Rac1 at a specific location within cells (Becker et al, 2013; Carmona-Fontaine et al, 2008a, 2008b; Matthews et al, 2008a, 2008b; Theveneau et al, 2010; Theveneau and Mayor, 2013). RhoA activates the cell’s cytoskeleton contraction, which is essential for retraction of the migratory cell’s trailing edge.…”

“…It is therefore possible that the cadherin-11 EC1–3 fragment may do the same. In addition, the depletion of the extracellular domain of cadherin-11 or the overexpression of the EC1–3 fragment in Xenopus leads to loss of CIL and directionality of the CNC (Abbruzzese et al, 2016; Becker et al, 2013). The intracellular domain of cadherin-11 has also a crucial function for CNC migration.…”

Ror2 signaling is required for local upregulation of GDF6 and activation of BMP signaling at the neural plate border

“…In the later phases of neural crest development, namely during migration, particularly β-catenin independent Wnt signaling plays a crucial role. The Wnt/planar cell polarity (PCP) pathway controls cell polarity, collective cell migration and the recently described contact inhibition of locomotion by local activation of the Rho family small GTPases RhoA and Rac1 (Becker et al, 2013;De Calisto et al, 2005;Matthews et al, 2008;Mayor and Theveneau, 2014;Shnitsar and Borchers, 2008).…”

Cranial Neural Crest Explants

“…CIL is essential for CNC migration both in vivo and in vitro. To assess CIL, one can perform a collision assay, in which two explants are placed in close proximity to one another (Becker et al 2013). CNC have been shown to be attracted by the growth factor Sdf-1, which is secreted by placodal ectoderm and is essential for their migration in vivo (Theveneau et al 2013).…”