Deregulated expression of c-Myc depletes epidermal stem cells

The beta -catenin/TCF signaling pathway is essential for the maintenance of epithelial stem cells in the small intestine(1). c-Myc a downstream target of beta -catenin/TCF (ref. 2), can induce differentiation of epidermal ste m cells in vitro(3). To determine the role of c-Myc in epidermal stem cells in vivo, we have targeted expression of human MYC2 to the hair follicles a nd the basal layer of mouse epidermis using a keratin 14 vector (K14,MYC2), Adult K14,MYC2 mice gradually lose their hair and develop spontaneous ulce rated lesions due to a severe impairment in wound healing; their keratinocy tes show impaired migration in response to wounding. The expression of beta 1 integrin, which is preferentially expressed in epidermal stem cells(4) is unusually low in the epidermis of K14.MYC2 mice. Label-retaining analysis to identify epidermal stem cells reveals a 75% reduction in the number of s tem cells in 3-month-old K14.MYC2 mice, compared with wildtype mice. We con clude that deregulated expression of c-Myc in stem cells reduces beta1 inte grin expression, which is essential to both keratinocyte migration and stem cell maintenance.