Control of keratinocyte growth and differentiation
Previous and current research
Mammalian epidermis is renewed throughout adult life by proliferation of stem cells and differentiation of their progeny. Epidermal stem cells give rise to the interfollicular epidermis, sebaceous gland and all the lineages of the hair follicle. Stem cells are of central importance in the genesis of epithelial tumours, since as permanent tissue residents they have the potential to accumulate oncogenic mutations over many years.
My laboratory is studying the factors that regulate the behaviour of cells (keratinocytes) in the epidermis. To do this we use a variety of approaches. We perform clonal analysis on human keratinocytes transduced with retroviral vectors to modulate gene expression. We generate transgenic mice with constitutive or inducible gene expression or deletion in the epidermis. We perform microarray analysis and we examine human tumour material.
We have identified markers of the stem cell compartment and demonstrated that stem cells have a highly patterned distribution. We have shown that integrin extracellular matrix receptors regulate keratinocyte proliferation and differentiation and we are mapping the downstream signalling pathways. Rac1 is required to maintain epidermal stem cells, while c-Myc stimulates stem cell progeny to differentiate. β-catenin controls the size of the stem cell compartment and regulates lineage selection through interactions with other signalling pathways such as Hedgehog, Notch and Vitamin D receptor pathways. Perturbation of integrin or β-catenin signalling contributes to the development of keratinocyte tumours in mice and humans.
Future projects
We wish to answer the following questions:
- How do stem cells make the decision to remain in the stem cell compartment or differentiate?
- What determines lineage selection?
- How is the spatial organisation of stem cells and their progeny established and maintained?
- How do stem cells and their neighbours contribute to the development of cancer?
