Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris

Abstract

In patients with pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell–cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmogleins in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 −/− mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. These mice were normal at birth, but by 8–10 d weighed less than DSG3 +/− or +/+ littermates, and at around day 18 were grossly runted. We speculated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies showed erosions with histology typical of PV, including suprabasilar acantholysis and “tombstoning” of basal cells. EM showed separation of desmosomes. Traumatized skin also had crusting and suprabasilar acantholysis. Runted mice showed hair loss at weaning. The runting and hair loss phenotype of DSG3 −/− mice is identical to that of a previously reported mouse mutant, balding (bal). Breeding indicated that bal is coallelic with the targeted mutation. We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation. These results demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia and suggest that pemphigus autoantibodies might interfere directly with such a function.

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…In contrast, DSC3 ablation resulted in preimplantation lethality, suggesting a desmosome-independent role during early development (Den et al 2006). Similarly, ablation of DSG isotypes revealed distinct functions in vivo: Whereas the DSG2 KO was embryonic lethal (Eshkind et al 2002), DSG3 KO mice showed weakened desmosomal adhesion, leading to the separation of keratinocytes (Koch et al 1997). The loss of DSG1 function has so far not been analyzed in mice as it requires deletion of all three DSG1 genes.…”

Desmocollin switching in colorectal cancer

“…The desmosomal cadherins (DCs), of which there are seven in humans, three desmocollins (Dsc1 -3) and four desmogleins (Dsg1-4), are membrane-spanning adhesion molecules of desmosomes. Genetic ablation of Dsc1 and Dsg3 results in epidermal blistering in transgenic mice, illustrating the importance of these molecules for the maintenance of normal intercellular adhesion (Koch et al, 1997;Chidgey et al, 2001). Loss of expression of DCs has been documented in various cancers (see Chidgey, 2002;Biedermann et al, 2005;Oshiro et al, 2005) and overexpression of DCs in nonadhesive cultured fibroblasts generates adhesion and inhibits invasion (Tselepis et al, 1998), supporting the idea that DCs have a tumour suppressor role.…”

Broken hearts, woolly hair, and tattered skin: when desmosomal adhesion goes awry

“…In 1997, Koch et al reported the first targeted ablation of a desmosomal cadherin, Dsg3, which is allelic to the naturally occurring balding mouse [8]. Dsg3 knockout mice are runted, display hair loss due to failure of telogen club hair anchorage, and recapitulate many of the aspects of the autoimmune disease pemphigus vulgaris such as oral blistering.…”