Contribution of desmosomal cadherins to tissue homeostatis of intestine and liver
Zusammenfassung der Projektergebnisse
The goal of the project was to examine the contribution of the cell-cell adhesion molecule desmoglein 2 (Dsg2) to the function of desmosome-mediated intercellular adhesion in differentiated tissues. Since we had previously observed that Dsg2 depletion results in peri-implantation lethality in mice, we generated mice with "floxed" desmoglein 2 (DSG2) alleles to conditionally induce targeted DSG2 gene mutation. The initial goal was to study the consequences on altered Dsg2 protein expression in the liver and intestine. We did not observe overt phenotypic alterations in both organs but, instead, noted the development of severe heart disease in cardiomyocyte-specific and constitutive DSG2 mutants, which presented features of arrhythmogenic right ventricular cardiomyopathy (ARVC). During the course of our project, DSG2 mutations were identified in ARVC patients. Given the unique chance of having a highly suitable model for this disease, we decided to change the focus of the project by studying the effects of DSG2 mutation in the murine heart. Collectively, the negative effects of DSG2 mutation on cardiac integrity and function became evident at time points, when demands on cardiac activity were highly increased, i.e. during embryonic development, when the circulatory system starts to operate, and in postnatal life, between 2 and 4 weeks, when heart and body weight increase approximately threefold. Full penetrance of symptoms was detected in animals by 6-8 weeks. We could distinguish an early disease stage characterized by functional compensation of the mutation-induced mechanical stress, the acute onset of disease at 2-4 weeks postnatally characterized by lesion formation with cardiomyocyte death leading to aseptic inflammation and fibrotic repair processes. The chronic disease phase from 8 weeks onwards was characterized by slow disease progression with continued slight increase in immune cells, altered force distribution and permanent myocardial reorganization, which eventually led to cardiac insufficiency. Many of these features are shared by human DSG2-related ARVC patients. Overall, our observations do not support a pathogenesis that relies on altered signaling through perturbed plakoglobin localization and pathological trans-differentiation as proposed. Instead, we suggest that deficient cardiomyocyte adhesion is an initial event, which induces a stress response and leads to necrosis upon decompensation.
Projektbezogene Publikationen (Auswahl)
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2007. Konditionale Mutagenese von Desmoglein in der Maus. Universität Mainz. Dissertation:
Holthöfer B
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2009. Murine Desmoglein 2-Mutanten als Tiermodell zur Untersuchung der arrhythmogenen rechtsventrikulären Kardiomyopathie. Universität Gießen. Dissertation:1-124. Göringer L. 2010. Expressionsmuster desmosomaler Cadherine in der Maus. Dissertation, Universität Mainz
Hofe V
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2010. Desmoglein 2-mediated adhesion is required for intestinal epithelial barrier integrity. Am J Physiol Gastrointest Liver Physiol 298:G774-783
Schlegel N, Meir M, Heupel W-M, Holthöfer B, Leube RE, Waschke J
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2011. Desmoglein 2 mutant mice develop cardiac fibrosis and dilation. Basic Res Cardiol 106:617-633
Krusche CA, Holthöfer B, Hofe V, van de Sandt AM, Eshkind L, Bockamp E, Merx MW, Kant S, Windoffer R, Leube RE
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2012. Histological and ultrastructural abnormalities in murine desmoglein 2-mutant hearts. Cell Tissue Res 348:249-259
Kant S, Krull P, Eisner S, Leube RE, Krusche CA
