| First Author | Rimpler U | Year | 2014 |
| Journal | PhD Thesis - Humboldt University zu Berlin | Mgi Jnum | J:302593 |
| Mgi Id | MGI:6509026 | Citation | Rimpler U (2014) Funktionelle Charakterisierung von Desmocollin 2 wahrend der Embryonalentwicklung und im adulten Herzen in der Maus. PhD Thesis - Humboldt University zu Berlin |
| abstractText | Desmosomes are highly organized adhesive intercellular junctions providing mechanical strength and structural stability to several tissues such as skin and heart. The adhesive core of desmosomes is formed by the transmembrane glycoproteins desmocollins (Dsc) and desmogleins (Dsg) which link neighbouring cells via interaction with their extracellular cadherin domains, while their intracellular portions interact with the cytoplasmic plaque components. In the developing embryo the relatively late appearance of desmosomal cadherins at the 32-cell stage coincident with the first formation of desmosomes is thought to be a key regulator of desmosome assembly. In the adult animal, desmocollin 2 and desmoglein 2 are the predominant isoforms ubiquitously expressed in all desmosome bearing tissues including the heart.To elucidate the role of Dsc2 for establishment and maintenance of desmosome adhesion and tissue integrity, we generated a constitutive knockout model of the mouse. The effect of gene inactivation was characterized under basal as well as under stress conditions, using two different stress models. Our data demonstrate that Dsc2 is not required for pre- and postnatal development. Dsc2-/- mice were viable and showed no pathological alterations at embryonic or adult stages. Consistently, Dsc2 deficient cardiomyocytes exhibited distinct and ultrastructural well organized desmosomes. However, mutant hearts displayed a decreased stress resistance. Increased mechanical pressure led to a significant reduction of cardiac function in Dsc2-/- animals. As observed by expression studies, the early loss of Dsc2 did not result in a compensatory upregulation of alternative adhesion molecules. This suggests that the transcellular link in Dsc2-/- desmosomes is mediated by the formation of isoformspecific Dsg2 dimers. Hence, cardiac dysfunction of Dsc2-/- animals may be the direct consequence of a decreased desmosomal adhesion, due to the reduced affinity of homophilic trans-interactions between Dsg2 molecules. In summary, our results demonstrate for the first time in vivo that Dsc2 is not essential for embryonic development and for the establishment and maintenance of distinct and well organized desmosomes. However, the reduced cardiac function in stressed knockout-mice suggests a crucial importance of Dsc2 for desmosomal adhesive strength. |
