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First published online February 23, 2005
doi: 10.1242/10.1242/jcs.01689
Research Article |
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Author for correspondence (e-mail: a.sonnenberg{at}nki.nl)
Accepted 16 December 2004
The 
6ß4 integrin is located at the basal surface of keratinocytes, in hemidesmosomal structures that mediate stable adhesion of epidermal cells to the underlying basement membrane component laminin-5. The absence of 6ß4 integrin causes junctional epidermolysis bullosa, a severe blistering disease of the skin leading to perinatal death, confirming its essential role in mediating strong keratinocyte adhesion. Several studies have suggested that 6ß4 integrin can also regulate signaling cascades that control cell proliferation, survival and migration through a mechanism independent of its adhesive function. We have generated a conditional knockout mouse strain, in which the gene encoding the ß4 integrin subunit (Itgb4) was inactivated only in small stretches of the skin. These mice were viable and permitted an accurate analysis of the consequences of the loss of ß4 on various biological processes by comparing ß4-positive and -negative parts of the skin in the same animal. Despite the complete loss of hemidesmosomes in regions lacking 6ß4 integrin, the distribution of a range of adhesion receptors and basement membrane proteins was unaltered. Moreover, loss of 6ß4 did not affect squamous differentiation, proliferation or survival, except for areas in which keratinocytes had detached from the basement membrane. These in vivo observations were confirmed in vitro by using immortalized keratinocytes – derived from ß4-subunit conditional knockout mice – from which the gene encoding ß4 had been deleted by Cre-mediated recombination. Consistent with the established role of 6ß4 in adhesion strengthening, its loss from cells was found to increase their motility. Our findings clearly demonstrate that, after birth, epidermal differentiation, proliferation and survival all proceed normally in the absence of 6ß4, provided that cell adhesion is not compromised.
Key words: Integrin, Epidermis, Knockout, Hemidesmosome, Adhesion, Proliferation
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