Stem cell renewal and lineage selection in adult mammalian epidermis. (360G-Wellcome-079894_Z_06_Z)

Adult mammalian epidermis is maintained by stem cells, which self-renew and produce progeny that differentiate along the hair follicle, sebaceous gland and interfollicular epidermal lineages. Two important regulators are Myc and b-catenin. Myc activation causes stem cell depletion and differentiation into interfollicular epidermis and sebaceous gland. b-catenin controls lineage choice in a dose-dependent fashion and acts by upregulating Hedgehog, Notch and EphB/ephrinB signalling. Focusing on these pathways, and exploiting Tamoxifen-inducible epidermal transgenes, my aims for the next 5 years are to answer the following questions. What are the consequences of modulating the strength and duration of individual signals, and how do different signalling pathways intersect? By what mechanisms does a single transcription factor, Myc, exert different effects on stem cells and differentiated cells? Can stem cells be generated from committed progenitors? Is the location of hair follicles and patterning along their radial axis fixed prior to birth, or subject to continuous regulation? How do epidermal cells communicate with dermal papilla cells and melanocytes to support epidermal function? The epidermis is an experimentally tractable tissue and the answers I obtain will provide a paradigm for understanding how stem cell number and lineage selection are controlled in other adult tissues.