Contribution of desmosomal cadherins to tissue homeostatis of intestine and liver

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The dynamic relationship between cell adhesion, differentiation and proliferation is of paramount importance for tissue homeostasis. Desmosomes are prominent adhesion sites in epithelial tissues mediating mechanical stability by anchoring the keratin intermediate filament cytoskeleton. In addition, it has been suggested that desmosomal components contribute to cell differentiation and participate in growth regulation. To test the various desmosomal functions in vivo, we have generated transgenic mice that allow temporally-defined and cell type-restricted depletion of the desmosomespecific cell-cell adhesion molecule desmoglein 2 either in enterocytes or hepatocytes. The goal of the project is to understand how the loss of desmoglein 2 affects desmosome formation and, more importantly, how compromised desmosomal adhesion influences the properties and dynamic behaviour of cell types with either low or high proliferative activity (i.e., enterocytes and hepatocytes, respectively) in health and disease. To this end, we will compare clinical features, histopathology, cell adhesion, cytoskeletal organisation, growth, and gene transcription in mice lacking desmoglein 2 in the intestine and liver. In addition, using chemical and genetic tumor models we will determine how the altered phenotypes affect tissue reactivity, tumor growth, tumor differentiation, and malignant transformation.