PDGF controls contact inhibition of locomotion by regulating N-cadherin during neural crest migration

Abstract

A fundamental property of neural crest (NC) migration is contact inhibition of locomotion (CIL), a process by which cells change their direction of migration upon cell contact. CIL has been proven to be essential for NC migration in amphibians and zebrafish by controlling cell polarity in a cell contact-dependent manner. Cell contact during CIL requires the participation of the cell adhesion molecule N-cadherin, which starts to be expressed by NC cells as a consequence of the switch between E-and N-cadherins during epithelial-to-mesenchymal transition (EMT). However, the mechanism that controls the upregulation of N-cadherin remains unknown. Here, we show that platelet-derived growth factor receptor alpha (PDGFRα) and its ligand platelet-derived growth factor A (PDGF-A) are co-expressed in migrating cranial NC. Inhibition of PDGF-A/PDGFRα blocks NC migration by inhibiting N-cadherin and, consequently, impairing CIL. Moreover, we identify phosphatidylinositol-3-kinase (PI3K)/AKT as a downstream effector of the PDGFRα cellular response during CIL. Our results lead us to propose PDGF-A/ PDGFRα signalling as a tissue-autonomous regulator of CIL by controlling N-cadherin upregulation during EMT. Finally, we show that once NC cells have undergone EMT, the same PDGF-A/PDGFRα works as an NC chemoattractant, guiding their directional migration.

Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization

“…Our finding that Girdin is involved in actin remodeling at the cell‐cell interface in A431 cancer cell groups (Figure C) supports the model, but it is unknown at present whether it was a direct or indirect effect of Girdin depletion. Another intriguing mechanism for collective migration is that cells maintain CIL to avoid interfering with their neighbors . We previously showed that the Girdin CT domain also binds the cell polarity regulator partitioning‐defective gene 3, which is known to be critical for collective migration and CIL by downregulating actomyosin contractility at cell‐cell contact (Figure E) .…”

“…Recent studies have begun to reveal the mechanisms of collective invasion of cancer by using in vitro culture models as well as studies of collective migration of cells during embryonic development . These include the contact inhibition of locomotion (CIL) that keeps the integrity of cell‐cell contact and spatially regulated trafficking of cell adhesion proteins such as N‐cadherin . We previously reported that the collective movement of cancer cell groups requires the expression of integrin β1 by the leading cells but not the following cells .…”

Exposure to sub-lethal dose of a combination insecticide during early embryogenesis influences the normal patterning of mesoderm resulting in incomplete closure of ventral body wall of chicks of domestic hen

“…The expression of E-cadherins during embryonic development happens quite early where they play a role in adhesion and compaction of the blastomeres. It also signals the controlled epithelial-to-mesenchymal conversion and regulates developmental processes like cell migration and proliferation [ [31] , [32] , [33] , [34] ]. The migration of mesodermal cell is favoured by downregulation of the E-cadherin and loss of cell adhesion [ [35] , [36] ].…”

Cellular organization and boundary formation in craniofacial development

“…At cell–cell contacts, N‐cadherin signaling function inhibits Rac1 activity and thus inhibits protrusions while promoting Rac1 activation and protrusions at the cellular free edge (Theveneau et al, ). Recently, it was shown that N‐cadherin expression is dependent on PDGFRα/PDGF‐A signaling (Bahm et al, ). The PDGFRα receptor tyrosine kinase and its ligand PDGFA are co‐expressed in CNCCs, and their inhibition prevents N‐cadherin expression, thus resulting in a loss of CIL and inhibiting NCC migration (Bahm et al, ).…”

“…Recently, it was shown that N‐cadherin expression is dependent on PDGFRα/PDGF‐A signaling (Bahm et al, ). The PDGFRα receptor tyrosine kinase and its ligand PDGFA are co‐expressed in CNCCs, and their inhibition prevents N‐cadherin expression, thus resulting in a loss of CIL and inhibiting NCC migration (Bahm et al, ). This pathway therefore achieves cell‐autonomous regulation of CIL by upregulating N‐cadherin during EMT.…”