Cadherin de-adhesion: consequences and mechanisms

Abstract

Cell-to-cell cadherin adhesions play an important role in regulating the behaviour of neural progenitor cells as well as providing the structural framework of the niche in which they reside. Cadherin de-adhesion can occur aberrantly and has significant consequences on the regulation of neural progenitor cells and disease progression. This work specifically investigated what are the consequences of cadherin de-adhesion on neural progenitor cell positioning and how changes in positioning affect neural progenitor cell maintenance. Cadherin de-adhesion was induced in the hindbrains of chick embryos through the expression of dominant negative N-cadherin and γ-catenin, two important components of cadherin adhesion. Cadherin de-adhesion caused the mispositioning of neural progenitor cells outside of the niche, this change in positioning resulted in diminished proliferation and activation of cell death. The results suggest cadherin adhesions control the positioning of neural progenitor cells and are a fundamental component of the neural progenitor cell niche. Cadherin de-adhesion also inhibited the induction of homeodomain expression in ventral neural progenitor cells, which is likely due to a reduction of notch signalling in the niche and subsequent de-sensitisation of neural progenitor cells to Shh. A model for cadherin adhesions as spatial regulators of neural progenitor cell maintenance is proposed. The mechanisms of how cadherin de-adhesion occurs remain poorly described and this work explored the significance of changes in calcium-cadherin binding in cadherin de-adhesion. This work demonstrated that an extracellular acidic pH alters calcium-cadherin binding interactions, which negatively affects cadherin-mediated cell adhesion. Additionally, cadherin calcium-binding sites are shown to be promiscuous to other metal ions but cadherin function is not. Cell aggregation, trypsin protection, and FRET binding assays demonstrated that the close calcium analogue, the trivalent ion of the lanthanide element terbium, can bind to cadherin calcium-binding sites but cannot induce rigid and adhesive cadherin molecules. Trivalent terbium, which has been previously proposed as an anti-cancer agent, therefore inhibits cadherin-mediated cell adhesion by competitive binding with calcium at cadherin calcium-binding sites. Together, the results reveal how changes to calcium-cadherin binding interactions affect cadherin adhesion and the possible significance of such changes to cadherin de-adhesion in cancer is described