J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/06/1091/12 $2.00
Volume 137, Number 5, June 2, 1997 1091-1102

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

Peter J. Koch,^* M G. Mahoney,^* Hiroyasu Ishikawa, Leena Pulkkinen, Jouni Uitto, Leonard Shultz,^§ George F. Murphy,^* Diana Whitaker-Menezes,^* and John R. Stanley^*

^* Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104;  Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107; and ^§ The Jackson Laboratory, Bar Harbor, Maine 04609

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.

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• Anhalt, G. J., Diaz, L. A. (2001). Research Advances in Pemphigus. JAMA 285: 652-654 [Abstract] [Full Text]  
• Nguyen, V. T., Ndoye, A., Bassler, K. D., Shultz, L. D., Shields, M. C., Ruben, B. S., Webber, R. J., Pittelkow, M. R., Lynch, P. J., Grando, S. A. (2001). Classification, Clinical Manifestations, and Immunopathological Mechanisms of the Epithelial Variant of Paraneoplastic Autoimmune Multiorgan Syndrome: A Reappraisal of Paraneoplastic Pemphigus. Arch Dermatol 137: 193-206 [Abstract] [Full Text]  
• Angst, B., Marcozzi, C, Magee, A. (2001). The cadherin superfamily: diversity in form and function. J. Cell Sci. 114: 629-641 [Abstract]  
• Koch, P. J., de Viragh, P. A., Scharer, E., Bundman, D., Longley, M. A., Bickenbach, J., Kawachi, Y., Suga, Y., Zhou, Z., Huber, M., Hohl, D., Kartasova, T., Jarnik, M., Steven, A. C., Roop, D. R. (2000). Lessons from Loricrin-deficient Mice: Compensatory Mechanisms Maintaining Skin Barrier Function in the Absence of a Major Cornified Envelope Protein. JCB 151: 389-400 [Abstract] [Full Text]  
• Nguyen, V. T., Ndoye, A., Grando, S. A. (2000). Novel Human {alpha}9 Acetylcholine Receptor Regulating Keratinocyte Adhesion is Targeted by Pemphigus Vulgaris Autoimmunity. Am. J. Pathol. 157: 1377-1391 [Abstract] [Full Text]  
• Wong, P., Colucci-Guyon, E., Takahashi, K., Gu, C., Babinet, C., Coulombe, P. A. (2000). Introducing a Null Mutation in the Mouse K6{alpha} and K6{beta} Genes Reveals their Essential Structural Role in the Oral Mucosa. JCB 150: 921-928 [Abstract] [Full Text]  
• Presland, R. B., Dale, B. A. (2000). Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease. CROBM 11: 383-408 [Abstract] [Full Text]  
• Fan, J.-L., Memar, O., McCormick, D. J., Prabhakar, B. S. (1999). BALB/c Mice Produce Blister-Causing Antibodies Upon Immunization with a Recombinant Human Desmoglein 3. J. Immunol. 163: 6228-6235 [Abstract] [Full Text]  
• Udey, M. C., Stanley, J. R. (1999). Pemphigus--Diseases of Antidesmosomal Autoimmunity. JAMA 282: 572-576 [Full Text]  
• Kowalczyk, A. P., Hatzfeld, M., Bornslaeger, E. A., Kopp, D. S., Borgwardt, J. E., Corcoran, C. M., Settler, A., Green, K. J. (1999). The Head Domain of Plakophilin-1 Binds to Desmoplakin and Enhances Its Recruitment to Desmosomes. IMPLICATIONS FOR CUTANEOUS DISEASE. J. Biol. Chem. 274: 18145-18148 [Abstract] [Full Text]  
• Heinonen, S, Mannikko, M, Klement, J., Whitaker-Menezes, D, Murphy, G., Uitto, J (1999). Targeted inactivation of the type VII collagen gene (Col7a1) in mice results in severe blistering phenotype: a model for recessive dystrophic epidermolysis bullosa. J. Cell Sci. 112: 3641-3648 [Abstract]  
• Bonne, S, van Hengel, J, Nollet, F, Kools, P, van Roy, F (1999). Plakophilin-3, a novel armadillo-like protein present in nuclei and desmosomes of epithelial cells. J. Cell Sci. 112: 2265-2276 [Abstract]  
• Gallicano, G. I., Kouklis, P., Bauer, C., Yin, M., Vasioukhin, V., Degenstein, L., Fuchs, E. (1998). Desmoplakin Is Required Early in Development for Assembly of Desmosomes and Cytoskeletal Linkage. JCB 143: 2009-2022 [Abstract] [Full Text]  
• Botchkarev, V. A., Welker, P., Albers, K. M., Botchkareva, N. V., Metz, M., Lewin, G. R., Bulfone-Paus, S., Peters, E. M. J., Lindner, G., Paus, R. (1998). A New Role for Neurotrophin-3 : Involvement in the Regulation of Hair Follicle Regression(Catagen). Am. J. Pathol. 153: 785-799 [Abstract] [Full Text]  
• Nguyen, V. T., Lee, T. X., Ndoye, A., Shultz, L. D., Pittelkow, M. R., Dahl, M. V., Lynch, P. J., Grando, S. A. (1998). The Pathophysiological Significance of Nondesmoglein Targets of Pemphigus Autoimmunity: Development of Antibodies Against Keratinocyte Cholinergic Receptors in Patients With Pemphigus Vulgaris and Pemphigus Foliaceus. Arch Dermatol 134: 971-980 [Abstract] [Full Text]  
• Tselepis, C., Chidgey, M., North, A., Garrod, D. (1998). Desmosomal adhesion inhibits invasive behavior. Proc. Natl. Acad. Sci. USA 95: 8064-8069 [Abstract] [Full Text]  
• Ahmad, W., Faiyaz ul Haque, M., Brancolini, V., Tsou, H. C., ul Haque, S., Lam, H., Aita, V. M., Owen, J., deBlaquiere, M., Frank, J., Cserhalmi-Friedman, P. B., Leask, A., McGrath, J. A., Peacocke, M., Ahmad, M., Ott, J., Christiano, A. M. (1998). Alopecia Universalis Associated with a Mutation in the Human hairless Gene. Science 279: 720-724 [Abstract] [Full Text]  
• Koch, P., Mahoney, M., Cotsarelis, G, Rothenberger, K, Lavker, R., Stanley, J. (1998). Desmoglein 3 anchors telogen hair in the follicle. J. Cell Sci. 111: 2529-2537 [Abstract]  
• Norvell, S., Green, K. (1998). Contributions of extracellular and intracellular domains of full length and chimeric cadherin molecules to junction assembly in epithelial cells. J. Cell Sci. 111: 1305-1318 [Abstract]  
• Nguyen, V. T., Ndoye, A., Grando, S. A. (2000). Pemphigus Vulgaris Antibody Identifies Pemphaxin. A NOVEL KERATINOCYTE ANNEXIN-LIKE MOLECULE BINDING ACETYLCHOLINE. J. Biol. Chem. 275: 29466-29476 [Abstract] [Full Text]  
• Chidgey, M., Brakebusch, C., Gustafsson, E., Cruchley, A., Hail, C., Kirk, S., Merritt, A., North, A., Tselepis, C., Hewitt, J., Byrne, C., Fassler, R., Garrod, D. (2001). Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation. JCB 155: 821-832 [Abstract] [Full Text]  

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