Plectin is a cytoskeletal protein that networks several filament systems and anchors them to the cell membrane. Because of these properties, plectin is important to maintain the integrity of cells and protect them against mechanical stress. Humans carrying certain mutations in the plectin gene do not produce plectin and develop epidermolysis bullosa simplex (EBS) and muscular dystrophy. These symptoms confirm the importance of plectin for epithelial (skin) and muscle cells.

One way to investigate the role of plectin in epithelial cells is to inactivate plectin in these cells, analyse how the mutated cells behave and compare them to their normal counterparts. The most complete way to do such an analysis is by generating a mouse that lacks plectin altogether and then study the physical and behavioural characteristics of the resulting mouse line. Another group had previously developed such a mouse line but this is not suitable for research purposes since the mice die after two days.

In this project a mouse model will be developed that has a normal life span, but in which the inactivation of the plectin gene can be controlled. This is possible, using modern genetic techniques, if the inactivating machinery is kept silenced during the gestation period or until the animal has reached adulthood. In this work, a mouse that has the peculiarity of carrying the plectin gene flanked by sites that allow the exchange of genetic material will be crossed with a mouse carrying the enzyme needed for the excision of this gene. If this enzyme, which is called Cre-recombinase, is only active in specific sets of cells, for example skin cells, plectin will be missing only from those cells. A further refinement of the system enables the activation of the recombinase to be controlled by the administration of a drug, either orally or as a cream.

Mice with an inducible disruption of the plectin gene in basal keratinocytes will be useful in showing the function of plectin in the skin, studying skin blistering under different stress conditions, and as a disease model for plectin-linked EBS.

FINANCIAL SUMMARY