A role for Syndecan-4 and PCP signalling in controlling directional migration of neural crest cells in vivo

The neural crest (NC) is an embryonic population of cells, which delaminate from the neural tube epithelium to become vigorous migratory cells that colonise the entire embryo and give rise to many different derivatives. Neural crest migration requires activation of the non-canonical Wnt/planar cell polarity (PCP) signalling pathway, but it is not known exactly how this pathway controls cell migration. Here I show that the PCP ligand, Wnt11R, and the downsteam PCP element, Dishevelled, are essential for neural crest migration in Xenopus laevis embryos. Additionally, the proteoglycan, Syndecan-4, interacts with Dishevelled to control NC migration. A detailed examination of neural crest cell behaviour in Xenopus and zebrafish embryos shows that, in the absence of Dishevelled or Syndecan-4, cells are motile but lack the persistent migration that allows them to reach their target tissue. Furthermore, Dishevelled and Syndecan-4 control directional migration by regulating the polarised formation of cell protrusions. They also regulate the formation of paxillin-containing focal contacts in vitro and in vivo. Rho GTPase activity was measured using FRET analysis in neural crest cells migrating in vitro and in vivo after interfering with Syndecan-4/PCP signalling. I demonstrate that Syndecan-4 acts as a potent inhibitor of Rac, while Dishevelled activates RhoA. In addition, I show that RhoA inhibits Rac in neural crest cells. So, modulation of Rac by Syndecan-4 and PCP signalling allows the polarised formation of cell protrusions required for persistent NC migration. Finally I show that cell-cell contact inhibition of locomotion, dependent on PCP signalling, contributes to the initial polarity of the cell by inhibiting cell protrusions. Thus I present a model whereby neural crest cells are able to establish and maintain a directed migration by the integration of signals from cell-cell interactions mediated by PCP signalling and from the extracellular matrix via Syndecan-4.EThOS - Electronic Theses Online ServiceGBUnited Kingdo