Wound healing is a complex process that is undertaken to prevent infection and severe dehydration after injury to the skin. Restoration of barrier function is essential, and a major contribution to this repair is skin re-epithelialization---the migration of keratinocytes into the wound site and subsequent establishment of a new stratified epidermis. Keratinocytes at the wound edge are said to undergo "activation", a process that involves changes in cell shape, reorganization of cell-cell contacts and alterations in keratin protein profiles. During activation, there is an upregulation of keratin 6 (K6), keratin 16 (K16), and keratin 17 (K17), together with a reduction in keratins 1 (K1) and 10 (K10). These changes occur at the wound edge within hours after injury and prior to any cell migration, raising the possibility that K6, K16, and K17 play an important role in wound re-epithelialization. We found that the ability to induce K6, K16 and K17 in response to injury is acquired at an early stage of the morphogenesis of skin epithelia during development, ahead of differentiation-related gene expression. The importance of this induction is underscored by the wound closure delay observed in K17 null embryos. Later during development, K6 and K17 occur in the periderm, a specialized layer of cells at the embryo surface. Periderm cells participate in the formation of temporary epithelial fusions at the level of eyelids, digits, and ear. This phenomenon is similar to wound repair in adult skin. To complement these studies, we developed an ex vivo skin explant culture assay that enables a quantitative assessment of the epithelialization potential of mature skin keratinocytes. Using this assay, we found that enhanced levels of K16 delay keratinocyte migration, while others found that the loss of K6 (and partial loss of K16) accelerates it. These findings led us to propose a model whereby the properties of epithelial cells in terms of resilience and malleability are optimized in a context-dependent manner, in part through differential expression of keratin proteins. Our model predicts that expression of K6, K16, and K17 is optimal for the effective migration of keratinocytes into a wound site
