Dominant mutations in p63, a transcription factor expressed as six isoforms, underlie the skin fragility syndrome ankyloblepharon ectodermal dysplasia and defting (AEG). Skin erosions that resemble those found in AEG patients develop in mice with reduced Delta-Np63 expression. The proposed studies will dissect the regulatory pathways by which Delta-Np63 controls normal epidermal homeostasis and will provide insight into the disease mechanism underlying AEG. We have recently identified Fras1 and Galml4 as direct transcriptional targets of Delta-Np63. Misexpression of these genes may contribute to the AEG phenotype. To further study the role of these genes in embryonic and postnatal skin, we will develop mouse models in which the expression of these genes is altered. These mouse models will allow us to determine the role of Frasi in regulating basement membrane integrity in postnatal epidermis. Furthermore, we will use these mouse models to determine the role of Calml4 in epidermal terminal differentiation. Our analysis of Calml4 function in keratinocyte terminal differentiation will be completed by performing proteomics and microarray analysis. Ultimately, the proposed studies will contribute to our understanding of the molecular mechanisms that cause skin fragility in AEG patients, and may identify targets for novel therapeutic approaches aimed at treating this disease.

Public Health Relevance

Skin erosions in patients with a skin fragility disease, AEG syndrome, are caused by mutations in a gene called p63. We have recently developed a mouse model for this disease which will allow us to determine how defects in p63 cause skin erosions. These studies may lead to the development of novel therapeutic strategies for this disease and other diseases characterized by fragile skin.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Baker, Carl
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University of Colorado Denver
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United States
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Koster, Maranke I; Dinella, Jason; Chen, Jiangli et al. (2014) Integrating animal models and in vitro tissue models to elucidate the role of desmosomal proteins in diseases. Cell Commun Adhes 21:55-63
Koch, Peter J; Dinella, Jason; Fete, Mary et al. (2014) Modeling AEC-New approaches to study rare genetic disorders. Am J Med Genet A 164A:2443-54
Ferone, Giustina; Thomason, Helen A; Antonini, Dario et al. (2012) Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome. EMBO Mol Med 4:192-205
Mikkola, M L; Costanzo, A; Thesleff, I et al. (2010) Treasure or artifact: a decade of p63 research speaks for itself. Cell Death Differ 17:180-3; author reply 184-6
Koster, Maranke I (2010) p63 in skin development and ectodermal dysplasias. J Invest Dermatol 130:2352-8
Koster, Maranke I; Marinari, Barbara; Payne, Aimee S et al. (2009) DeltaNp63 knockdown mice: A mouse model for AEC syndrome. Am J Med Genet A 149A:1942-7
Koster, Maranke I (2009) Making an epidermis. Ann N Y Acad Sci 1170:7-10
Beaudry, Veronica G; Pathak, Navneeta; Koster, Maranke I et al. (2009) Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis. Am J Med Genet A 149A:1952-7
Kim, Soeun; Choi, Irene F; Quante, Jessica R et al. (2009) p63 directly induces expression of Alox12, a regulator of epidermal barrier formation. Exp Dermatol 18:1016-21