The question of which pathways regulate the differentiation of the stratified epidermis has been central to epithelial biology. Transcription is one of the most important regulatory mechanisms controlling the stepwise program of epidermal differentiation. Epidermis has been used as an excellent model for studying 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. Our research effort have focused in characterizing the regulation and function of Dlx3 homeobox transcription factor, a member of the murine Dlx family, with essential roles in epidermal, osteogenic and placental 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 judged by the upregulation of expression of late differentiation markers such as loricrin and filaggrin. We are assessing the role of Dlx3 in modulating the cell cycle during the epidermal differentiation process using cultured keratinocytes and mouse models with inducible-ectopic expression of Dlx3. Recent results have also indicated that epidermal deletion of the Dlx3 homeodomain transcription factor leads to disruption of the barrier formation and is linked to the development of an inflammatory response characterized by the accumulation of IL-17-producing CD4(+) T, CD8(+) T, and γδT cells in the skin and lymph nodes. The gene expression signature of this conditional mouse model shared features with lesional psoriatic skin, and Dlx3 expression was markedly and selectively decreased in psoriatic skin. Utilizing a mouse model we are studying the effects of endogenous excess of retinoic acid on developing skin and the molecular and cellular events that lead to defects in skin morphology and differentiation.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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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
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
Duverger, Olivier; Beniash, Elia; Morasso, Maria I (2016) Keratins as components of the enamel organic matrix. Matrix Biol 52-54:260-265
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
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
Bible, Paul W; Kanno, Yuka; Wei, Lai et al. (2015) PAPST, a User Friendly and Powerful Java Platform for ChIP-Seq Peak Co-Localization Analysis and Beyond. PLoS One 10:e0127285
Ha, Hye-Lin; Wang, Hongshan; Pisitkun, Prapaporn et al. (2014) IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proc Natl Acad Sci U S A 111:E3422-31
Isaac, J; Erthal, J; Gordon, J et al. (2014) DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo. Cell Death Differ 21:1365-76
Huebner, Aaron J; Dai, Daisy; Morasso, Maria et al. (2012) Amniotic fluid activates the nrf2/keap1 pathway to repair an epidermal barrier defect in utero. Dev Cell 23:1238-46
Okano, Junko; Lichti, Ulrike; Mamiya, Satoru et al. (2012) Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development. J Cell Sci 125:1827-36

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