DESMOCOLLIN 1 IN EPIDERMAL DEVELOPMENT & HOMEOSTASIS

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DESCRIPTION: (verbatim) -- Desmosomes are cell adhesion structures (junctions) that are particularly abundant in the epidermis. The importance of these junctions for normal skin function was clearly demonstrated by the finding that mutations in several genes encoding desmosomal proteins cause skin diseases. Furthermore, in certain autoimmune diseases, pathogenic autoantibodies inhibit normal desmosome function, thereby causing blistering skin diseases. Desmosomes in the upper layers of the epidermis contain desmocollin 1 (dsc1) which, together with desmoglein 1, forms the transmembrane core of this junction. Dsc1 is expressed in two isoforms (dsc1a, dsc1b), that are generated by alternative splicing of the pre-mRNA. Progress has been made in recent years in understanding some of the molecular interactions of dsc1 with other desmosomal proteins. However, studies addressing the in vivo function of these proteins are still forthcoming. Furthermore, based on its proposed role in desmosome formation and function, we hypothesize that mutations in dsc1 might lead to skin disease in humans. The following specific questions will be addressed: Is dsc1 essential for the formation of a functional desmosomal adhesion complex in the epidermis and, if so, does the absence of one or both splice variants lead to a skin phenotype resembling known "adhesion diseases" or fragility syndromes? What are the individual contributions of the two dsc1 splice variants (a and b) to desmosome function, i.e., cell adhesion and anchoring of the intermediate filament cytoskeleton to the cell membrane? Is the amino-terminal domain of dsc1, like that of desmogleins, crucial for its function in vivo? To address these questions, we will generate knock out / knock in mice that are deficient for one or both dsc1 splice variants. Furthermore, we will generate mice that express an amino-terminally truncated dsc1 with a deletion of amino acid sequences in the EC1 and EC2 domains. The animal models proposed here will not only provide answers regarding the normal function of dsc1 in vivo, but also simulate disease phenotypes and help identify human diseases that might be caused by impaired dsc1 function.