Disruption of Keratin Networks Causes Blistering

The epidermis is a tough outer layer of tissue, which acts as a water-tight barrier to prevent desiccation and serves as a protection against abrasion. In epidermal cells, bundles of keratin filaments are cross-linked by filaggrin, an IFAP, and are anchored at their ends to desmosomes. As epidermal cells differentiate, the cells condense and die, but the keratin filaments remain intact, forming the structural core of the dead, keratinized layer of skin. The structural integrity of keratin is essential in order for this layer to withstand abrasion.

In humans and mice, the K4 and K14 keratin iso-forms form heterodimers that assemble into protofilaments. A mutant K14 with deletions in either the N- or the C-terminal domain can form heterodimers in vitro but does not assemble into protofilaments. The expression of such mutant keratin proteins in cells causes IF networks to break down into aggregates. Transgenic mice that express a mutant K14 protein in the basal stem cells of the epidermis display gross skin abnormalities, primarily blistering of the epidermis, that resemble the human skin disease epidermolysis bullosa simplex (EBS). Histological examination of the blistered area reveals a high incidence of dead basal cells. Death of these cells appears to be caused by mechanical trauma from rubbing of the skin during movement of the limbs. Without their normal bundles of keratin filaments, the mutant basal cells become fragile and easily damaged, causing the overlying epidermal layers to delaminate and blister (Figure 19-37). Like the role of desmin filaments in supporting muscle tissue, the general role of keratin filaments appears to be to maintain the structural integrity of epithelial tissues by mechanically reinforcing the connections between cells. I

▲ EXPERIMENTAL FIGURE 19-37 Transgenic mice carrying a mutant keratin gene exhibit blistering similar to that in the human disease epidermolysis bullosa simplex.

Histological sections through the skin of a normal mouse and a transgenic mouse carrying a mutant K14 keratin gene are shown. In the normal mouse, the skin consists of a hard outer epidermal layer covering and in contact with the soft inner dermal layer. In the skin from the transgenic mouse, the two layers are separated (arrow) due to weakening of the cells at the base of the epidermis. [From P Coulombe et al., 1991, Cell 66:1301; courtesy of E. Fuchs.]

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