Loss of alpha6 integrins in keratinocytes leads to an increase in TGFbeta and AP1 signaling and in expression of differentiation genes

Mice lacking the alpha6 integrin chain die at birth with severe skin blistering. To further study the function of alpha6 integrin in skin, we generated conditionally immortalized cell lines from the epidermis of wild-type and alpha6 deficient mouse embryos. Mutant cells presented a decreased adhesion on laminin 5, the major component of the basement membrane in the skin, and on laminins 10/11 and 2. A DNA array analysis revealed alterations in the expression of extracellular matrix (ECM) components including laminin 5, cytoskeletal elements, but also membrane receptors like the hemidesmosomal components integrin beta4 and collagen XVII, or growth factors and signaling molecules of the TGFbeta, EGF, and Wnt pathways. Finally, an increase of several epidermal differentiation markers was observed in cells and tissue at the protein level. Further examination of the mutant tissue revealed alterations in the filaggrin signal. These differences may be linked to an upregulation of the TGFbeta and the Jun/Fos pathways in mutant keratinocytes. These results are in favor of a role for integrin alpha6beta4 in the maintenance of basal keratinocyte properties and epidermal homeostasis.