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.
Highlights
One of the most migratory cell types during early vertebrate development is cells of the neural crest (NC)
platelet-derived growth factor A (PDGF-A) and PDGFRα are co-expressed in the NC and are required for NC migration We first analysed the expression of PDGFRα and platelet-derived growth factor (PDGF)-A by in situ hybridization and RT-PCR
The expression of PDGFRα in the NC was further confirmed by immunostaining (Fig. 1K) and western blotting (Fig. 1L,M). These data strongly support the notion that PDGF-A and PDGFRα are coexpressed in the migrating NC
Summary
One of the most migratory cell types during early vertebrate development is cells of the neural crest (NC). Disruption of NC cell migration during development can lead to pathologies including craniofacial abnormalities, heart malformation and colonic aganglionosis (Hirschprung’s disease), R.M., 0000-0001-9053-9613 EMT in Xenopus and zebrafish cranial NC is defined by an acquisition of CIL, which has been linked to a switch from E- to N-cadherin ( known as cadherins 1 and 2, respectively) (Scarpa et al, 2015) This Ncadherin upregulation has been shown to be essential for CILdependent polarity in NC collective migration (Mayor and EtienneManneville, 2016; Theveneau et al, 2010, 2013). The specific mechanism by which PDGF controls the formation of NC-derived tissues has not been completely elucidated
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