Role of catenin signalling in adult epidermal cell fate specification.

The epidermis is maintained through self-renewal of stem cells and differentiation of their progeny into interfollicular epidermis, hair follicles and sebaceous glands. In order to investigate the role of P-catenin in cell fate selection in adult epidermis I used a drug- regulated system to activate P-catenin signalling at specific stages of the hair cycle and for different lengths of time in the epidermis of transgenic mice. I found that following P-catenin activation resting hair follicles are recruited into the growth phase of the hair cycle, and new ectopic hair follicles form from existing hair follicles, interfollicular epidermis and sebaceous glands. The ectopic follicles grow in number and size to form trichofolliculomas. While a transient activation of p-catenin signalling is sufficient to trigger hair follicle morphogenesis, continuous activation is required to maintain hair follicle tumours, and titration of P-catenin signalling influences the quantity and timing of ectopic hair follicle formation. The new hair follicles form without major perturbation of the existing stem cell compartment, contain dermal papillae, undergo cycles of growth and regression, and express markers of the epidermal stem cell niche. Microarray analysis of the P-catenin induced genes suggested a role for the Hedgehog (Hh) and Notch pathways and vitamin D receptor downstream of P-catenin. I was able to investigate also the relationship between p> catenin and c-Myc in epidermal cell lineage choice. Finally, I developed an in vitro model for the analysis of lineage selection at the single cell level. I demonstrate the advantage of temporal, spatial and dosage control of p-catenin signalling to analyse the effects of its activation in adult epidermis and to investigate epidermal stem cell self-renewal and differentiation, an approach that could be applied more broadly to look at the interaction between multiple pathways in adult skin homeostasis