Desmosomes are highly dynamic cell-cell adhesion complexes that have the ability to adjust their adhesive properties and molecular composition, thereby affecting cell migration, cell sorting and cell differentiation. One mechanism by which this is achieved is a change in the ratio of desmosomal cadherins [desmocollins (Dsc) and desmogleins (Dsg)] that are assembled into the desmosome. Very little is known about the gene regulatory pathways that control desmosome function during skin and skin appendage development. The goal of the present application is to determine how the expression of the Dsc genes is regulated during skin appendage (e.g. hair follicles, mammary gland) development. We have already identified transcription factors from the Wnt, NFkB and Notch signaling pathways that differentially regulate Dsc genes in cultured cells. To test our hypothesis that these transcription factors also control Dsc gene expression in cultured keratinocytes and in developing skin appendages, we propose the following specific aims: 1.) To analyze the effects of major signal transduction pathways on the expression of desmocollins in vitro. 2.) To determine the effects of Wnt Signaling on Dsc2 and Dsc3 gene expression during development. 3.) To use an in vivo complementation assay to determine whether Wnt signaling is required for Dsc3 function in vivo. The results of this project will lead to a better understanding of how morphogenetic processes, such as appendage formation, are regulated during development. Furthermore, understanding the regulation of desmosomal genes will help to develop new concepts in the therapy of acquired and inherited diseases caused by impaired desmosome function. Project Narrative: The goal of this project is to identify gene regulatory pathways that control desmosome function during mammalian development, in particular pathways that control the formation of the skin and its appendages (e.g. hair follicles, mammary glands).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053892-05
Application #
8225295
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2008-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$374,430
Indirect Cost
$122,914
Name
University of Colorado Denver
Department
Dermatology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
O'Shea, Charlene; Fitzpatrick, James E; Koch, Peter J (2014) Desmosomal defects in acantholytic squamous cell carcinomas. J Cutan Pathol 41:873-9
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
Dinella, Jason; Koster, Maranke I; Koch, Peter J (2014) Use of induced pluripotent stem cells in dermatological research. J Invest Dermatol 134:e23
Tokonzaba, Etienne; Chen, Jiangli; Cheng, Xing et al. (2013) Plakoglobin as a regulator of desmocollin gene expression. J Invest Dermatol 133:2732-40
Chen, Jiangli; O'Shea, Charlene; Fitzpatrick, James E et al. (2012) Loss of Desmocollin 3 in skin tumor development and progression. Mol Carcinog 51:535-45
Schulze, Katja; Galichet, Arnaud; Sayar, Beyza S et al. (2012) An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris. J Invest Dermatol 132:346-55
Neuber, Steffen; Muhmer, Mario; Wratten, Denise et al. (2010) The desmosomal plaque proteins of the plakophilin family. Dermatol Res Pract 2010:101452
Ganeshan, Radhika; Chen, Jiangli; Koch, Peter J (2010) Mouse models for blistering skin disorders. Dermatol Res Pract 2010:584353