Date of Award
Doctor of Philosophy (PhD)
The spectacular cellular rearrangements of keratinocytes as epidermal appendages form and the epidermis turns over rely on the rapid and precise modulation of intercellular adhesion. While genetic studies in vertebrates have revealed a pivotal role for classical cadherin-mediated cell adhesion in the regulation of coordinated cell movements in the embryo, little is know about the contribution of classical cadherins to epidermal morphogenesis. Genetic dissection of cadherin function in skin is complicated by overlapping expression of E- and P-cadherin and the fact that their genes are tightly linked, precluding conventional conditional knockout strategies. I have combined conditional gene ablation, in vitro analysis of de novo epithelial sheet formation, and transgenic RNA interference to overcome these issues in order to define the contribution of classical cadherins in epidermal physiology. Loss of E-cadherin in the skin epithelium revealed striking differences by which epidermis and hair follicles handle the loss of this critical protein, a feature I have traced to the compensatory upregulation of P-cadherin in the E-cadherin null epidermal basal layer but not the hair follicle. To formally test this premise, I have examined the in vitro and in vivo consequences of E- and P-cadherin inhibition. Suppression of classical cadherins blocked epidermal sheet formation in vitro, while overexpression of either E- or P-cadherin rescued these defects, defining cadherin level, rather than subtype, as a critical factor in this process. Classical cadherin inhibition in vivo was not compatible with survival and resulted in perturbations in tissue integrity, increased apoptosis, and defects in epidermal barrier. This analysis has uncovered striking defects not observed previously in single loss of function mutations for E- and P-cadherin and has revealed a critical role of classical cadherins in skin biology. Finally, by contrasting loss-of-function mutants of epidermal catenins and cadherins, I have further defined a number of cadherin dependent and independent roles of adherens junction components in the epidermis. The ability to clearly dissociate cadherin and catenin functions and to identify regulatory processes governing their interaction should prove useful in the context of both development and disease.
Tinkle, Christopher, "Dissecting the Functions of Classical Cadherins in Skin" (2009). Student Theses and Dissertations. 256.