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Transcriptional Control of Epidermal Morphogenesis
Research in my lab is aimed at identifying the signaling pathways that control epidermal development and differentiation. The epidermis is the outermost component of the skin and functions as a barrier protecting the body from dehydration, mechanical trauma, and microbial insults. This barrier function is established during embryogenesis and is the result of a complex and precisely coordinated stratification program. Whereas the morphological changes that occur during epidermal development have been extensively studied, the molecular mechanisms that control this process remain poorly understood. A key regulator of epidermal development is p63, a transcription factor that is expressed as six different isoforms. Mice lacking all p63 isoforms do not develop an epidermis or skin appendages, such as hair follicles and mammary glands. Using genetically engineered mice, my laboratory studies the role of p63 isoforms during embryonic development and postnatal differentiation of the skin. Our goal is to identify the molecular pathways that are initiated by p63 and to further study their role in the epidermis. In further support of the importance of p63 during normal epidermal development, p63 mutations have been identified in a subset of patients with ectodermal dysplasias. Ectodermal dysplasias are inherited disorders that are characterized by abnormalities of the skin and skin appendages. One of these ectodermal dysplasias is characterized by severe skin fragility. As a consequence of this fragile skin, patients with this disorder often develop large skin erosions which are painful and predispose affected individuals to infections. We have recently developed a mouse model for this ectodermal dysplasia, which we are using to further study the pathogenic mechanisms that underlie skin fragility in patients with this disorder. Selected Publications
Koster, M.I., Kim, S., Mills, A.A., DeMayo, F.J., and Roop, D.R. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 18(2):126-31, 2004. Koster, M.I., Kim, S., Huang., J., Williams, T., and Roop, D.R. TAp63α induces AP-2γ as an early event in epidermal morphogenesis. Dev Biol. 289(1): 253-261, 2006. Nguyen, B.C., Lefort, K., Mandinova, A., Antonini, D., Devgan, V., Della Gatta, G., Koster, M.I., Zhang, Z., Wang, J., Tommasi di Vignano, A., Kitajewski, J., Chiorino, G., Roop D.R., Missero, C., and Dotto, G.P. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 20(8):1028-42, 2006. Koster, M.I., Lu, S.L., Wang, X.J., and Roop, D.R. Reactivation of developmentally expressed p63 isoforms accelerates tumor development and progression. Cancer Res. 66(8):3981-6, 2006. Keyes, W.M., Vogel, H., Koster, M.I., Guo, X., Qi, Y., Petherbridge, K.M., Roop, D.R., Bradley, A., and Mills, A.A. p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Proc Natl Acad Sci U S A. 103(22):8435-40, 2006. Koster, M.I., Dai, D., Marinari, B., Sano, Y., Costanzo, A., Karin, M., and Roop, D.R. p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci USA, 104(9):3255-60, 2007. Koster, M.I., Dai, D., and Roop, D.R. Conflicting roles for p63 in skin development and carcinogenesis. Cell Cycle 6(3):269-273, 2007. Koster, M.I. and Roop, D.R. Mechanisms regulating epithelial stratification. Ann Rev Cell Dev Biol., 23:93-113, 2007. |
Faculty
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