Analysis of stem cell fate decisions in epidermis by in vivo lineage marking

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The best-characterized stem cell compartment in mouse epidermis is in the hair follicle bulge. DNA label-retaining cells (LRC) cluster in this region, where expression of the previously reported stem cell markers CD34 and keratin 15 also is high. It has been suggested that LRC likely only represent a subset of the stem cells that are present in the epidermis. In this study, I propose using permanent, in vivo lineage marking to assess the potential of epidermal stem cells in normal skin, under circumstances where epidermal development is disturbed due to aberrant expression of members of the Wnt/ -catenin pathway, and during tumour formation. In addition, I will characterize the nature of a population of hair follicle keratinocytes that are identified by the cell surface marker MTS24. These keratinocytes give rise to large colonies with great efficiency when cultured at low density in vitro. MTS24-positive cells will be characterized with respect to their self-renewal capacity, ability to differentiate into different lineages both in vitro and in vivo, and global gene expression pattern. MTS24-positive cells are localized in an uncharacterized region of the hair follicle between the bulge and the sebaceous glands. Keratinocytes located in this region tend not to be label retaining and lack expression of CD34 and keratin 15. To compare the lineage potential of keratinocytes derived from the MTS24-positive region of the hair follicle to those derived from the bulge, transgenic mice will be generated which target an activatable form of Cre to each of these two regions. Taken together, the studies described in this proposal will demonstrate the utility of in vivo differential somatic cell marking to address key questions in epidermal biology. This approach will be used to characterize whether a new population of keratinocytes represent a new reservoir of epidermal stem cells or a population of lineage-restricted progenitor cells.