Skin and hair follicle integrity is crucially dependent on β1 integrin expression on keratinocytes

Abstract

beta 1 integrins are ubiquitously expressed receptors that mediate cell-cell and cell-extracellular matrix interactions. To analyze the function of beta1 integrin in skin we generated mice with a keratinocyte-restricted deletion of the beta 1 integrin gene using the cre-loxP system. Mutant mice developed severe hair loss due to a reduced proliferation of hair matrix cells and severe hair follicle abnormalities. Eventually, the malformed hair follicles were removed by infiltrating macrophages. The epidermis of the back skin became hyperthickened, the basal keratinocytes showed reduced expression of alpha 6 beta 4 integrin, and the number of hemidesmosomes decreased. Basement membrane components were atypically deposited and, at least in the case of laminin-5, improperly processed, leading to disruption of the basement membrane and blister formation at the dermal-epidermal junction. In contrast, the integrity of the basement membrane surrounding the beta 1-deficient hair follicle was not affected. Finally, the dermis became fibrotic. These results demonstrate an important role of beta 1 integrins in hair follicle morphogenesis, in the processing of basement membrane components, in the maintenance of some, but not all basement membranes, in keratinocyte differentiation and proliferation, and in the formation and/or maintenance of hemidesmosomes.

Induction of phenotype modifying cytokines by FERMT1 mutations

“…Interestingly, dermal fibrosis similar to KS has been observed in mice with keratinocyte-restricted deletion of integrin beta−1, which exhibited basement membrane defects, macrophage infiltration, increased expression of TGF-β1, CTGF and tenascin-C, and dermal fibrosis (Brakebusch, et al, 2000). In that case the molecular mechanisms were not explored.…”

β1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis

“…In progeny, the cre mediates ablation of the conditional ␤1 integrin allele and activates a promoterless lacZ reporter gene inserted downstream of the second loxP site (for details, see Brakebusch et al 2000;Potocnik et al 2000). Col2a1-cre/␤1 fl/wt mice show no abnormalities.…”

Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues

“…The K5 Cre recombinase transgene was made by cloning the lambda bacteriophage Cre recombinase cDNA into a plasmid containing the bovine K5 promoter (Ramirez et al, 1994;Brakebusch et al, 2000). Founder transgenic mice were made by injecting the purified transgene into the pronuclei of zygotes, and then implanting the zygotes into pseudo-pregnant female mice.…”

“…A K5 Cre recombinase transgene was generated by subcloning the bacteriophage Cre recombinase cDNA into a vector containing the bovine K5 promoter, the rabbit b-globin intron and the SV40 polyadenylation signal (Ramirez et al, 1994;Pierce et al, 1998a;Brakebusch et al, 2000). The K5 promoter drives expression of the Cre recombinase to the basal cell layer of the epidermis and several other epithelial tissues that have been shown to express Brca1 (Ramirez et al, 1994;Lane et al, 1995;Marquis et al, 1995;Pierce et al, 1998a).…”