Epithelial detachment due to absence of hemidesmosomes in integrin β4 null mice

Abstract

Integrins are heterodimeric transmembrane glycoproteins which are engaged in a variety of cellular functions, such as adhesion, migration and differentiation1. The integrin alpha 6 beta 4 is expressed on squamous epithelia, on subsets of endothelial cells, immature thymocytes and on Schwann cells and fibroblasts in the peripheral nervous system. In stratified epithelia, alpha 6 beta 4 is concentrated in specialised adhesion structures, called hemidesmosomes, which are implicated in the stable attachment of the basal cells to the underlying basement membrane by connecting the intermediate filaments with the extracellular matrix. The nature of the interactions between the various hemidesmosomal proteins, that lead to the formation of hemidesmosome is poorly understood. To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption. Homozygous beta 4 null mice died shortly after birth and displayed extensive detachment of the epidermis and other squamous epithelia. The dramatically reduced adhesive properties of the skin was accompanied by the absence of hemidesmosomes at the basal surface of keratinocytes. No evidence was found for impaired T-cell development, nor for defects in myelination in the peripheral nervous system.

Targeted inactivation of plectin reveals essential function in maintaining the integrity of skin, muscle, and heart cytoarchitecture

“…A reduction of integrin ␤4 expression also has been reported in mice deficient in integrin ␣6, another binding partner of integrin ␤4 (Georges- Labouesse et al 1996), whereas in integrin ␤4 (−/−) mice van der Neut et al 1996) a reduction in the expression of HD1 was noticed (van der Neut et al 1996). In addition, a recent report suggested that the subcellular distribution of HD1 is determined by the cytoplasmic domain of the ␤4 subunit (Sanchez-Aparicio et al 1997), arguing in favor of a direct interaction between plectin and integrin ␤4 within the hemidesmosomal complex.…”

Integrin alpha 6 beta 4 forms a complex with the cytoskeletal protein HD1 and induces its redistribution in transfected COS-7 cells.

“…The a6f34 integrin plays an important role in the assembly of hemidesmosomes (Vidal et al 1995;Dowling et al, 1996;Georges-Labouesse et al, 1996;Niessen et al, 1996;Van der Neut et al, 1996), and its association with HD1 may provide a link between the keratin filaments and the plasma membrane during early hemidesmosome formation. This role of HD1 /plectin is supported by the observation that in patients deficient for plectin/HD1 no keratin filaments are attached to hemidesmosomes (Gache et al, 1996;McLean et al, 1996;Smith et al, 1996).…”

The making of hemidesmosome structures in vivo

“…Targeted inactivation of hemidesmosome components in mouse shows that laminin-332 and a6b4-integrin are critical to construct stable hemidesmosomes (Table 2A) (Georges-Labouesse et al, 1996;van der Neut et al, 1996;Ryan et al, 1999;Meng et al, 2003). Their absence leads to severe skin blistering and near absence of hemidesmosomes, although reduced amounts of BP230, BP180, and plectin can still associate with the basal membrane.…”