Regulation Of Epidermal Differentiation

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

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Abstract

Epidermis has been used as an excellent model to study the process of cellular differentiation because the cells form a stratified structure during development, and each stratum is easily identified by morphology and expression of specific markers. Stratification of the epidermis is a process that continues to occur throughout the life of the organism. The process entails the outward movement of the proliferative basal cells that are adjacent to the basement membrane toward the surface of the skin. Our research efforts have focused on characterizing the regulation and function of the DLX3 homeobox transcription factor, a member of the murine DLX family, with essential roles in epidermal development. Transgenic temporal and spatial mis-expression of DLX3 in the pre-differentiated basal layer caused an abnormal skin phenotype, characterized by cessation of proliferation and premature differentiation of the basal cells. We have shown that DLX3 modulates the cell cycle progresion during epidermal differentiation using cultured keratinocytes and mouse models with inducible-ectopic expression of DLX3. We recently reported a novel DLX3-dependent network that modulates epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinquished during progression of experimentally induced mouse squamous cell carcinoma (SCC). These results establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis. Our results have also demonstrated that epidermal-specific deletion of the homeobox transcription regulator DLX3 disrupts keratinocyte differentiation, leads to disruption of the barrier formation and results in an IL-17 linked psoriasis-like skin inflammation. Recently, we defined the keratinocyte-intrinsic DLX3-dependent signals that lead to the IL-17 associated psoriatic-like skin inflammation. Utilizing a conditional tamoxifen-inducible system, we showed that inflammation triggering signals from DLX3-null keratinocytes and the reciprocal signaling crosstalk between epidermis and dermis induced infiltration of antigen-presenting cells and IL-17 producing T cells into the dermis. Our results demonstrate a direct link between DLX3 ablation and phosphorylation of STAT3 that results in rapid immune cell infiltration and development of skin inflammation. On studies of wound resolution, we performed a unique comparative analysis between human oral and cutaneous wound healing using paired and sequential biopsies during the repair process. Using molecular profiling, we determined that wound-activated transcriptional networks are present at basal state in the oral mucosa, priming the epithelium for wound repair. We showed that oral mucosal wound related networks control epithelial cell differentiation and regulate inflammatory responses, highlighting fundamental global mechanisms of repair and inflammatory responses in humans. The paired comparative analysis allowed for the identification of differentially expressed SOX2 and PITX1 transcriptional regulators in oral versus skin keratinocytes, conferring a unique identity to oral keratinocytes. We show that SOX2 and PITX1 transcriptional function has the potential to reprogram skin keratinocytes to increase cell migration and improve wound resolution in vivo. Our data provide insights into therapeutic targeting of chronic non-healing wounds based on greater understanding of the biology of healing in human mucosal and cutaneous environments.