TARGETED INACTIVATION OF PLECTIN REVEALS ESSENTIAL FUNCTION IN MAINTAINING THE INTEGRITY OF SKIN, MUSCLE, AND HEART CYTOARCHITECTURE

Previous studies suggest that plectin, a versatile cytoskeletal linker protein, has an important role in maintaining the structural integrit y of diverse cells and tissues. To establish plectin's function in a l iving organism, we have disrupted its gene in mice. Plectin (-/-) mice died 2-3 days after birth exhibiting skin blistering caused by degene ration of keratinocytes. Ultrastructurally, hemidesmosomes and desmoso mes appeared unaffected. In plectin-deficient mice, however, hemidesmo somes were found to be significantly reduced in number and apparently their mechanical stability was altered. The skin phenotype of these mi ce was similar to that of patients suffering from epidermolysis bullos a simplex (EBS)-MD, a hereditary skin blistering disease with muscular dystrophy, caused by defects in the plectin gene. In addition, plecti n (-/-) mice revealed abnormalities reminiscent of minicore myopathies in skeletal muscle and disintegration of intercalated discs in heart. Our results clearly demonstrate a general role of plectin in the rein forcement of mechanically stressed cells. Plectin (-/-) mice will prov ide a useful tool for the study of EBS-MD, and possibly other types of plectin-related myopathies involving skeletal and cardiac muscle, in an organism amenable to genetic manipulation.