Transcription is one of the most important regulatory mechanisms controlling the stepwise program of epidermal differentiation. 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-17associated 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 woundrelated 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 and nonhealing wounds based on greater understanding of the biology of healing in human mucosal and cutaneous environments.
| Iglesias-Bartolome, Ramiro; Uchiyama, Akihiko; Molinolo, Alfredo A et al. (2018) Transcriptional signature primes human oral mucosa for rapid wound healing. Sci Transl Med 10: |
| Bhattacharya, Shreya; Duverger, Olivier; Brooks, Stephen R et al. (2018) Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis. Exp Dermatol 27:289-292 |
| Li, Jin; Zheng, Le; Uchiyama, Akihiko et al. (2018) A data mining paradigm for identifying key factors in biological processes using gene expression data. Sci Rep 8:9083 |
| Bhattacharya, Shreya; Kim, Jin-Chul; Ogawa, Youichi et al. (2018) DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis. J Invest Dermatol 138:1052-1061 |
| Palazzo, Elisabetta; Kellett, Meghan D; Cataisson, Christophe et al. (2017) A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation. Cell Death Differ 24:717-730 |
| Iglesias-Bartolome, Ramiro; Morasso, Maria I (2017) Policing Tumorigenesis within the Skin: Good Outs Bad. Cell Stem Cell 21:419-420 |
| Bible, Paul W; Sun, Hong-Wei; Morasso, Maria I et al. (2017) The effects of shared information on semantic calculations in the gene ontology. Comput Struct Biotechnol J 15:195-211 |
| Palazzo, E; Kellett, M; Cataisson, C et al. (2016) The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth. Oncogene 35:3114-24 |
| Duverger, Olivier; Beniash, Elia; Morasso, Maria I (2016) Keratins as components of the enamel organic matrix. Matrix Biol 52-54:260-265 |
| Lessard, Juliane C; Kalinin, Alexandr; Bible, Paul W et al. (2015) Calmodulin 4 is dispensable for epidermal barrier formation and wound healing in mice. Exp Dermatol 24:55-7 |
Showing the most recent 10 out of 18 publications
