Research objectives and content
Cadherin-and integrin-mediated cell-cell and cell-matrix interactions are continuously reorganized during embryonic development to allow cell proliferation, migration and aggregation. The migration of neural crest cells throughout the embryo is accompanied by sequential modulations in their intercellular cohesion and thus provides a powerful paradigm for exploring the mechanisms of co-ordinated interplay between adhesion systems. The host laboratory has provided evidence that N-cadherin-based intercellular contacts are down-regulated during migration and that the integrins involved in cell migration can regulate directly N-cadherin activity through signalling. Interestingly, _-catenin is a possible target of this signalling pathway. _-catenin is associated with cadherins for promoting intercellular adhesion or, alternatively, is part of the W.nt signalling pathway and associates with the transcription factor LEF-1 in the nucleus for regulating gene expression. By analogy with the Wnt signalling pathway, we suggest that, in migrating neural crest cells, integrin signalling reduces N-cadherin-mediated cell-cell interaction and also causes the nuclear translocation of _-catenin with LEF-1, thus allowing transcription of genes essential for cell migration. The aim of the present project is to test this hypothesis and, more specifically, to analyse using both in vivo and in vitro approaches whether (i) in neural crest cells, the cellular localisation of _-catenin is under the control of integrins, (ii) the signalling activity of _-catenin is required for migration, (iii) Wnt signalling co-operates with integrin signalling to control _-catenin and N-cadherin functioning, and (iv) there exist genes essential for migration that are controlled by _-catenin. This study should allow us to demonstrate that, in addition to Wnt, integrins regulate the _-catenin signalling activity, and to identify genes that are specifically regulated during cell migration.
Training content (objective, benefit and expected impact)
After biochemical and cell biological studies on the structure-function relationship of laminin-binding integrins during my PhD, this project will give me the opportunity to investigate the interaction and co-ordination between adhesion molecules and the signalling pathways involved and allow me to develop a different and broader view on adhesion molecule functioning. An additional advantage of this project model system is that it will give me insight into developmental mechanisms. In practical terms, I will learn developmental biological techniques, such as manipulating (microsurgery) and analysing embryos, as well as retroviral transfection techniques and methods to study cell migration.
Links with industry / industrial relevance (22)