Mouse models for blistering skin disorders

Abstract

Genetically engineered mice have been essential tools for elucidating the pathological mechanisms underlying human diseases. In the case of diseases caused by impaired desmosome function, mouse models have helped to establish causal links between mutations and disease phenotypes. This review focuses on mice that lack the desmosomal cadherins desmoglein 3 or desmocollin 3 in stratified epithelia. A comparison of the phenotypes observed in these mouse lines is provided and the relationship between the mutant mouse phenotypes and human diseases, in particular pemphigus vulgaris, is discussed. Furthermore, we will discuss the advantages and potential limitations of genetically engineered mouse lines in our ongoing quest to understand blistering skin diseases.

Figure 1

Expression of the desmosomal cadherins desmoglein 1, 2, and 3 (DSG1–3) and desmocollin 1 and 3 (DSC1, 3) as well as α6-integrin (ITGA6) in the interfollicular epidermis and the tongue epithelium of mice: Immunofluorescence staining of newborn epidermis ((a), (e), (c), (g)) and adult tongue ((b), (d), (f), (h)). The cadherins are shown in green while the integrin is shown in red. ((i), (j), (k), (l)) Schematic representation of the distribution of each desmosomal cadherin in the epidermis ((i), (k)) and tongue epithelium ((j and l)). Note that DSC2 antibodies which recognize the mouse isoform are currently not available (see text for details). Immunofluorescence signals from the stratum corneum are due to nonspecific binding of secondary antibodies (white bar). Cell layers expressing the relevant proteins are marked with brackets. The white arrow in (g) points towards the basal layer, which does not synthesize DSC1. Note that the expression of DSG1 + 2 in the tongue is low in the basal layers. (i, j, k, l) Distribution of the desmosomal cadherins in stratified epithelia (BL, basal layer; SC, stratum corneum). High expression levels are symbolized by a broad base and low expression levels are symbolized by narrow tips.

Figure 2

Acantholysis in the interfollicular epidermis and mucous membranes of Dsc3 and Dsg3 null epithelia. (a) Acantholysis between the basal and first suprabasal layer in the back skin epidermis of newborn conditional Dsc3 null mice (Dsc3^fl/fl/K14-Cre). (b) Severe skin lesions of a 140 day-old Dsc3^fl/fl/K14-Cre mouse showing blistering in a healing wound. Note that these mice enter a cycle in which acantholysis triggers epithelial tongue formation and secondary blistering in the epithelium that covers the original wound. (c) Tongue section from a 25-day-old Dsg3 null mouse showing acantholysis and massive inflammation in the epithelium. (d) Vagina of a 6-month-old Dsg3 null mouse showing acantholysis in the deep epithelium (between basal and suprabasal layer). (e) Back skin of an adult wild type mouse. (f) Tongue histology of an adult wild type mouse. Stars indicate blister cavities.

Figure 3

Hair loss phenotype of conditional Dsc3 null ((a), (b), (c), (d)) and conventional Dsg3 null mice ((e), (f), (g), (h)). Both mouse lines show cyclic hair loss beginning around the time of weaning when the hair follicles on the back of the head enter telogen, the resting phase of the hair growth cycle. (a) Hair loss of a 56-day-old conditional Dsc3 null mouse and (b) a 53-day-old Dsg3 null mouse. (b and f) Acantholysis between the two cell layers surrounding the telogen hair club leads to loss of the hair shaft. Arrows indicate separation of the two cell layers. Note that early lesions are shown, that is, before the hair shaft is actually lost. (c and g) Telogen hairs with a single epithelial cell layer surrounding the club hair (brackets, nuclei of the epithelial sheet surrounding the clubs are stained in dark (c) and light (g) blue, resp.). In both cases, hair loss leads to the development of dermal cysts ((d and h); stars). Note that the hair loss in both mouse lines appears to follow the same mechanism, that is, loss of cell-cell adhesion between the two epithelial cell layers which anchor the telogen hair in the skin.