Dominant mutations in p63, a transcription factor expressed as six isoforms, underlie the skin fragility syndrome ankyloblepharon ectodermal dysplasia and clefting (AEC). I recently discovered that skin erosions that resemble those found in AEC 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 AEC. Using gene expression profiling, I have identified three putative Delta-Np63 target genes, Frasl, Frem2, and Calml4, whose misexpression may contribute to the AEC phenotype. During the mentored phase of the award I will determine if Delta-Np63alpha directly regulates expression of the basement membrane components Frasl and Frem2. In addition, I will determine if Delta-Np63alpha regulates keratinocyte differentiation by directly inducing expression of the predicted calcium-binding protein Calml4. These studies will be performed in the laboratory of Dr. Dennis Roop at Baylor College of Medicine, which has a long history of outstanding research and mentorship of young scientists. As an independent investigator, I will generate inducible mouse models in which expression of Frasl, Frem2, or Calml4 can be downregulated in the epidermis. These mouse models will allow me to determine the role of Frasl and Frem2 in regulating basement membrane integrity in postnatal epidermis. Furthermore, I will use these mouse models to determine the role of Calml4 in epidermal terminal differentiation. My analysis of CalirM 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 AEC patients, and may identify targets for novel therapeutic approaches aimed at treating this disease. ? ? Relevance: Skin erosions in patients with a skin fragility disease, AEC 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. ? ? ? ?
| 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 |
| 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 |
| 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 |
| 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 |
| Fete, Mary; vanBokhoven, Hans; Clements, Suzanne E et al. (2009) International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome. Am J Med Genet A 149A:1885-93 |
| Koster, Maranke I; Roop, Dennis R (2008) Sorting out the p63 signaling network. J Invest Dermatol 128:1617-9 |
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