alpha 3 beta 1 and alpha 6 beta 4 integrin receptors for laminin-5 are notessential for epidermal morphogenesis and homeostasis during skin development

Continuous regeneration and homeostasis of the stratified epidermis require s coordinated regulation of cell proliferation, cell differentiation, and c ell survival. Integrin-mediated cell adhesion to the extracellular matrix h as important roles in regulating each of these processes, Integrins alpha 3 beta 1 and alpha 6 beta 4 are both receptors on epidermal keratinocytes fo r the basement membrane protein laminin-5, the major ligand for epidermal a dhesion in mature skin. Ablation in mice of either alpha 3 beta 1 or alpha 6 beta 4, through null mutation of the gene encoding the alpha 3, alpha 6, or beta 4 integrin subunit, results in epidermal blistering of varying seve rity Our previous studies showed that, despite blistering, differentiation and stratification of the epidermis appeared essentially normal in mice tha t lacked either alpha 3 beta 1 or alpha 6 beta 4. However, these studies di d not definitively address the specific developmental importance of each in tegrin, since they may have overlapping and/or compensatory functions. Give n the individual importance of alpha 3 beta 1 or alpha 6 beta 4 in maintain ing the dermo-epidermal junction in mature skin, we sought to determine the importance of these integrins for embryonic skin development and epidermal morphogenesis. In the current study, me analyzed skin development in mutan t embryos that completely lack both integrins alpha 3 beta 1 and alpha 6 be ta 4. Although alpha 3 beta 1/alpha 6 beta 4-deficient embryos displayed ep idermal blistering by stage E15.5 of development, they also retained region s of extensive epidermal adhesion to the basement membrane through stage E1 6.5, indicating alternative adhesion mechanisms. Apoptosis was induced in d etached epidermis of alpha 3 beta 1/alpha 6 beta 4-deficient embryos, exemp lifying vividly the importance of epithelial attachment to the basement mem brane for cell survival. However, apoptotic cells were completely absent fr om attached epidermis of alpha 3 beta 1/alpha 6 beta 4-deficient embryos, s howing that epithelial adhesion that occurred independently of alpha 3 beta 1 and alpha 6 beta 4 also protected cells from apoptosis, Remarkably, in t he absence of the known laminin-5 binding integrins (alpha 3 beta 1, alpha 6 beta 4, and alpha 6 beta 1), keratinocytes retained the capacity to proli ferate in the epidermis, and epidermal stratification and skin morphogenesi s appeared normal prior to blister formation. These findings show that whil e alpha 3 beta 1 and alpha 6 beta 4 are both required for integrity of the dermo-epidermal junction, neither one is essential for epidermal morphogene sis during skin development.