Lack of plakoglobin in epidermis leads to keratoderma.
Loss-of-function mutation of Jup has been associated with Naxos disease, which is characterized by arrhythmogenic cardiomyopathy and the cutaneous disorder palmoplantar keratoderma. Previously, we have shown that genetic ablation of Jup in cardiomyocytes in mice leads to arrhythmogenic cardiomyopathy similar to Naxos disease in humans. Currently, to determine the pathogenesis of Naxos disease-associated keratoderma, we generated Jup mutant mice by inactivating Jup restrictively in keratinocytes. Jup mutant mice largely recapitulated the clinical features of human palmoplantar keratoderma: overcornification and thickening of the epidermis. Jup mutant mice also suffered skin ulceration and inflammation. Cell apoptosis and proliferation were significantly elevated in Jup mutant epidermis. Ultrastructural analyses revealed the disruption of the assembly of desmosomes and adherens junctions in Jup mutant epidermis. We also demonstrated the compensational increase in β-catenin at Jup mutant cell-cell junctions without altering its signaling activities. Our findings provide important insights for understanding the pathogenesis of human palmoplantar keratoderma.
Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Deqiang
D
Li
Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Wenjun
W
Zhang
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Ying
Y
Liu
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Laura S
LS
Haneline
Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202. Electronic address: wshou@iupui.edu.
Weinian
W
Shou
D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism*; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004817:Epidermis / Q000378:metabolism* / Q000648:ultrastructure; D006201:Hair Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism*
D051180:Desmoplakins; C495292:JUP protein, human; C495293:Jup protein, mouse; D051185:gamma Catenin