Laminins in the basement membrane of the skin
Laminins are building blocks for polymers and networks of basement membranes. At least three laminins (LM), LM-311, LM-332 and LM-511, are present in the basement membrane of the skin. LM-511 form “classical” polymers, while LM-332 provides the core of a unique network anchoring the epidermis to the dermis. The N-terminus of LM-332 associates with other components of the network, such as collagens VII and XVII, while the C-terminus interacts with cell surface receptors, in particular the a3b1 and a6b4 integrins. Genetic studies in human and mice indicated that tissue-bound LM-332 and a6b4 integrins are involved in the anchorage of the epidermis to the underlying dermis. In contrast, the physiological relevance of b1 integrins, soluble LM-332 and other extracellular matrix components is not clear. To address these issues, we used either RNA interference to down-regulate LM-332, b1 integrins and b1 integrin-associated proteins in cultivated keratinocytes or a mouse model with an inducible, keratinocyte-restricted silencing of the Lama3 gene. Interestingly, silencing either LM-332, a3 integrin or preventing full activation of b1 integrins compromises intercellular adhesion and collective migration, while enhancing single cell migration. Mechanistically this is linked to a role of b1 integrins in maintaining integrity of the cortical actin network and targeting b4 integrins to cell surface sites important for cell-matrix adhesions. Moreover, the keratinocytes respond by activating repair/regeneration mechanisms, including up-regulation of fibronectin, collagen receptor and pro-inflammatory cytokines.