Research Report 2010 - MDC

Graduate StudentsFlorian KirchnerManuela MagarinUte Rimpler*Robert ZinkeTimm Zörgiebel*Technical AssistantsIska LiebnerSigrid MilanElke, Nickel*Martin TaubeJana Treutler**part of the period reported(DCM) are also caused by mutations in sarcomere proteingenes our analyses support the concept of a sharedmolecular etiology of these different cardiomyopathicphenotypes.Mutations in the giant sarcomeric protein TTN areresponsible for inherited dilated cardiomyopathy (DCM)in humans. To dissect affected pathways leading totitin-based DCM and to investigate the role of titin incardiac development, we generated a mouse model thatmimics a TTN truncation mutation (c.43628insAT) previouslyidentified in a large family with autosomal dominantDCM. Heterozygous mice chronically exposed tocardiac stress displayed features of DCM, thereby recapitulatingthe human phenotype. The mutant embryoshomozygous for the Ttn knock-in mutation showedsevere defects in sarcomere formation and died beforeE9.5 due to non-beating hearts. Our data demonstratethat the removal of titin’s M-line region leads tounformed sarcomere structures and provide a chronologicalrelationship between titin expression, sarcomereformation, and embryonic lethality due to absent cardiaccontractile function.Regeneration of the embryonic heartJörg DrenckhahnRegeneration of functional myocardium after cardiacinjury is currently one of the most rapidly developingfields in cardiovascular research. Several differentapproaches based on injection of various cell types aswell as mobilisation or stimulation of endogenous cellsto repair the damaged heart have been reported.Despite lots of encouraging findings some controversialresults have highlighted the need for a better under-Figure 1. The structural organization of desmosomes. (A) The schematic drawingshows desmosomal cadherins (DSG, desmoglein; DSC, desmocollin); the armadillofamilymembers plakoglobin (PG) and the plakophilins (PKP); and the intermediatefilament (IF)-binding protein desmoplakin (DSP). (B) Electron micrograph ofdesmosomes from murine heart.Figure 2. Immunolocalisation of desmosomal proteinsPlakophilin2 (green) and Plakoglobin (red) inneonatal rat cardiomyocytes ; Nkx2.5 (magenta).Cardiovascular and Metabolic Disease Research 43