Turan, Melissa; (2021) Cell Matrix Adhesions and Collective Cell Migration: The Role of X-chef-1. Doctoral thesis (Ph.D), UCL (University College London.

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Abstract

Collective cell migration is involved in a plethora of developmental and physiological processes. One well-studied example is the collective migration of the cephalic neural crest (NC); an embryonic stem cell population that gives rise to a diverse cell lineage in vertebrate embryos. NC migration requires the formation of integrin-based cell matrix adhesions. However, the exact molecular composition of these adhesions and how they regulate cell polarity during NC migration remains unclear. Furthermore, it was recently demonstrated that stiffening of the migratory substrate is required to trigger the onset of NC migration. This finding raises the question of how the neural crest transduces mechanical cues from its substrate to trigger migration. Whilst integrin-based adhesions serve as the mechanosensory unit of adherent cells, their functional relevance in mechanotransduction during NC migration remains unknown. Here, we investigate the role of Crk Associated Substrate (CAS) protein, X-chef-1, within the cephalic neural crest in Xenopus laevis. This scaffolding protein within the integrin signaling pathway is expressed in the neural crest prior to the onset of migration, however its function is unknown. Through loss of function experiments, we investigated the requirement of X-chef-1 during NC migration. Knock down of X-chef-1 inhibited migration in vivo and cell dispersion and motility in vitro. Through the targeted expression of X-chef-1 dominant negative constructs, we observed that the migratory deficit was primarily attributed to the loss of tyrosine phosphorylation of the X-chef-1 substrate domain. Taken together, we propose that tyrosine phosphorylation of the X-chef-1 substrate domain promotes migration through activating the cell polarity effector Rac-1 at the leading edge of the neural crest. Furthermore, preliminary experiments suggested that constitutive phosphorylation of the X-chef-1 substrate domain may rescue NC migration on mechanically non-permissive substrates in vivo. Hence, our results set up the framework for further investigation into the role of X-chef-1 in the response to mechanical cues during NC migration.

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