We often aim to form, maintain and strengthen tight bonds with our neighbours, and our cells are no different. Reporting in the December issue of Nature Cell Biology, Elaine Fuchs and colleagues investigated how such bonds are formed, and provide evidence for the essential role of desmoplakin in this process.

Desmoplakin is a cytoskeletal-linker protein that is largely restricted to specialized cell–cell adhesion structures called desmosomes, which are abundant in epidermal cells. Desmosomal cadherins interact through molecules, such as desmoplakin, to link with the intermediate-filament network. As a rare human skin condition has been linked to haploinsufficiency of desmoplakin (that is, a loss of one of the two desmoplakin alleles), this protein seems to be essential for skin formation. Because of this, Fuchs and colleagues generated a conditional knockout of the gene to probe the functions of the desmoplakin protein.

The authors found that mice with this conditional knockout have severe epidermal defects — any stress applied to the skin causes intercellular separation and the skin peels away from the affected pups. At a cellular level, desmosomes lack any interactions with keratin filaments and have an altered composition. In addition, the lower layers of the epidermis have a weakend state of adhesion, which is evident in the splitting of desmosomes after trauma. In desmoplakin-null keratinocytes placed in tissue culture, the overall number of desmosomes is reduced and epidermal-sheet formation is defective.

Most surprisingly, these desmoplakin-null epidermal keratinocytes and epidermal cells from the conditional-knockout pups have a reduced number of adherens junctions. Adherens junctions are adhesion complexes composed of E-cadherins (green on figure) and catenins. They are distinct from desmosomes, and are linked to the actin cytoskeleton. Recent work has indicated that these two adhesion complexes might interact.

From the study of these mice and cells, it seems that desmoplakin is fundamentally important for organizing desmosomal proteins into functional adhesion structures and for maintaining the structure of the adherens junction. Once adherens junctions are formed and adhesive connections are made, desmosomes act to clamp the neighbouring cells together. This allows adhesion to be 'zipped up' through membrane sealing. Without desmosomes, neighbouring membranes cannot maintain strong adherens junctions or organization of the actin cytoskeleton. Both of these processes are necessary for cells to seal their membranes with their neighbours. Far from being the second-class citizens in intercellular adhesion, desmosomes must now stand shoulder-to-shoulder in our thinking on how our cells generate bonds with their neighbours.