UC Irvine

The epidermis, the outermost layer of the skin, continuously develops to form a tight epidermal barrier that is required for animal hydration and survival. Epidermal development occurs during embryogenesis via the mechanism of epidermal differentiation. We have previously described the role of the epidermal transcription factor Grainyhead like-3 (GRHL3) in epidermal differentiation and barrier formation. Additionally, we observed that mice lacking Grhl3 in the epidermis exhibit soft-tissue syndactyly between their digits, this phenomenon was also detected in Grhl3 germline knockouts (Grhl3KO). Through our work, we identified epithelial mechanisms required for normal digit separation during development. We discovered the formation of a multi-layered epithelial structure between the digits. In Grhl3KO embryos, the interdigital epithelia is fused, resulting in syndactyly. The separation of the epithelial structure depends on the anti-adhesive properties of the periderm, a transient layer located at the uppermost surface of the embryonic epidermis. We found that periderm cells in Grhl3 KO are hyper-adhesive with abnormal expression of adhesion molecules on their surfaces. Our findings reveal novel epithelial mechanisms required for digit separation; they also uncover a crucial role of Grhl3 in normal periderm development.

Adult skin is normally maintained in the absence of Grhl3. Our previous work indicated that Grhl3 is required for epidermal recovery after injury. Adult mice lacking Grhl3 in the epidermis exhibit impaired full-thickness wound healing and delayed keratinocyte migration. We observed an increase in cell-cell adhesion between follower cells at the wound-edge in Grhl3 cKO, concomitant with an increase expression of the adherens junction’s protein, E-cadherin. Gene expression analysis of Grhl3 cKO wounded-keratinocytes 3 days post wounding shows a significant downregulation of F-actin protein Fscn1, a protein known to negatively regulate the expression of E-cadherin. These data indicate a novel Grhl3-Fscn1 mechanism required for cell-cell loosening in follower cells during keratinocyte migration in wounding. In addition, we observed that early after wounding, Grhl3 cKO mice exhibit a defect in dermal vasodilation and decreased blood flow. Gene expression analysis of wounded-keratinocytes 24 hrs post wounding suggest that Grhl3 regulate the expression of enzymes required for the biosynthesis of vasodilator factor prostaglandin E2. These observations are intriguing and suggest a Grhl3-mediated vasodilation during cutaneous wound healing.