Hemidesmosome

Abstract: The alpha 6/beta 4 complex is a member of the integrin family of adhesion receptors. It is found on a variety of epithelial cell types, but is most strongly expressed on stratified squamous epithelia. Fluorescent antibody staining of human epidermis suggests that the beta 4 subunit is strongly localized to the basal region showing a similar distribution to that of the 230-kD bullous pemphigoid antigen. The alpha 6 subunit is also strongly localized to the basal region but in addition is present over the entire surfaces of basal cells and some cells in the immediate suprabasal region. By contrast staining for beta 1, alpha 2, and alpha 3 subunits was very weak basally, but strong on all other surfaces of basal epidermal cells. These results suggest that different integrin complexes play differing roles in cell-cell and cell-matrix adhesion in the epidermis. Immunoelectron microscopy showed that the alpha 6/beta 4 complex at the basal epidermal surface is strongly localized to hemidesmosomes. This result provides the first well-characterized monoclonal antibody markers for hemidesmosomes and suggests that the alpha 6/beta 4 complex plays a major role in epidermal cell-basement membrane adhesion. We suggest that the cytoplasmic domains of these transmembrane glycoproteins may contribute to the structure of hemidesmosomal plaques. Immunoultrastructural localization of the BP antigen suggests that it may be involved in bridging between hemidesmosomal plaques and keratin intermediate filaments of the cytoskeleton.

Abstract: Cell-extracellular matrix interactions have important roles in many biological processes, including embryonic development, growth control and differentiation. Integrins are the principal receptors for extracellular matrix1. They are composed of non-covalently associated α and β chains1. Integrin oc6 can associate with either β1 or β4 (refs 2,3). Both integrin complexes are receptors for laminins, major components of basement membranes2,3. The distribution of α6 (refs 4–10) as well as studies using function-blocking antibodies have suggested an essential role for this laminin receptor during embryogenesis, in processes such as endoderm migration4,5 or kidney tubule formation9. Here we report that, surprisingly, mice lacking the α6 integrin chain develop to birth. However, they die at birth with severe blistering of the skin and other epithelia, a phenotype reminiscent of the human disorder epidermolysis bullosa11. Hemidesmo-somes are absent in mutant tissue. This absence is likely to result from the lack of α6/β4, the only integrin in hemidesmosomes of stratified squamous and transitional epithelia12–14. Mutations in the genes encoding integrin β4 and chains of laminin-5 have been implicated in junctional epidermolysis bullosa15–18. Our study provides evidence that some forms of epidermolysis bullosa may originate from defects of the α6 gene.

Abstract: The integrin heterodimer alpha 6 beta 4 is expressed in many epithelia and in Schwann cells. In stratified epithelia, alpha 6 beta 4 couple with BPAG1-e and BPAG2 to form hemidesmosomes, attaching externally to laminin and internally to the keratin cytoskeleton. To explore the function of this atypical integrin, and its relation to conventional actin-associated integrins, we targeted the removal of the beta 4 gene in mice. Tissues that express alpha 6 beta 4 are grossly affected. Stratified tissues are devoid of hemidesmosomes, display only a very fragile attachment to the basal lamina, and exhibit signs of degeneration and tissue disorganization. Simple epithelia which express alpha 6 beta 4 are also defective in adherence, even though they do not form hemidesmosomes. In the absence of beta 4, alpha 6 is dramatically downregulated, and other integrins do not appear to compensate for the loss of this heterodimer. These data have important implications for understanding integrin function in cell-substratum adhesion, cell survival and differentiation, and for understanding the role of alpha 6 beta 4 in junctional epidermolysis bullosa, an often lethal human disorder with pathology similar to our mice.