Disease relevance of Tmod1

• Pathogenesis of dilated cardiomyopathy: molecular, structural, and population analyses in tropomodulin-overexpressing transgenic mice [1].
• Certain aspects of the in vivo signaling phenotype including increased paxillin phosphorylation could be recapitulated in vitro using neonatal rat cardiomyocytes infected with recombinant adenovirus to overexpress tropomodulin [2].
• METHODS: Combinatorial effects of hypertrophy and dilation were investigated by cross-breeding of two cardiomyopathic transgenic mouse lines which develop either hypertrophy (calcineurin-mediated) or dilation (tropomodulin-mediated) [3].
• Mitochondrial respiration was unaffected in tropomodulin-overexpressing transgenic mice, another model of cardiomyopathy [4].

High impact information on Tmod1

• Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart [5].
• Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length [6].
• Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice [6].
• The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium [6].
• Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs [6].

Biological context of Tmod1

• In the absence of Tmod1, embryonic development appeared normal up to embryonic day (E) 8 [7].
• We conclude that Tmod1 is required for regulation of actin filament lengths and myofibril maturation; this is critical for heart morphogenesis during embryonic development [7].
• Our data indicate that differentiating ES cells are a powerful system to investigate the functional properties of contractile proteins and that Tmod1 functions are critical for late stages of myofibrillogenesis, and for the maturation of myofibrils [8].
• Strikingly, in vitro cardiomyocyte differentiation of wild type (WT) ES cells faithfully recapitulates in vivo cardiomyocyte differentiation, allowing us to evaluate the phenotypes of Tmod1 knockout (KO) myofibrils irrespective of embryonic lethality of Tmod1 KO mice [8].
• The tropomodulin (Tmod) gene maps to chromosome 4, closely linked to Mup1 [9].

Anatomical context of Tmod1

• Here, we investigated myofibril assembly and heart development in a Tmod1 knockout mouse [7].
• Disruption in the tropomodulin1 (Tmod1) gene compromises cardiomyocyte development in murine embryonic stem cells by arresting myofibril maturation [8].
• Immunofluorescence and electron microscopy studies revealed that Tmod1 null cardiac myocytes were round, morphologically immature, and contained underdeveloped myofibrils that were shorter, narrower, and had fewer thin filaments than those in WT cells [8].
• Identical Tmod cDNAs were cloned from mouse brain, skeletal muscle, heart, and hematopoeitic cells [10].
• Genomic blotting demonstrates that Tmod is encoded by a single gene, which has a 1077-bp open reading frame that is highly homologous to that of the human erythrocyte [10].

Physical interactions of Tmod1

• Erythrocyte tropomodulin (E-Tmod) stabilizes short actin protofilaments in erythrocytes and caps longer sarcomeric actin filaments in striated muscles [11].

Regulatory relationships of Tmod1

• Paxillin, the target substrate molecule for focal adhesion kinase phosphorylation, was redistributed in tropomodulin-overexpressing transgenic hearts with enhanced paxillin phosphorylation and cleavage [2].

Other interactions of Tmod1

• Tropomodulin1 (Tmod1) caps thin filament pointed ends in striated muscle, where it controls filament lengths by regulating actin dynamics [7].
• The sensory ganglia and epithelia of the inner ear express Tmod mRNA as do other sensory neurons such as those in the olfactory epithelium [10].
• Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice [12].
• These events were studied in tropomodulin-overexpressing transgenic mice that develop dilated cardiomyopathy associated with chronic elevation of intracellular calcium [2].
• Augmenting the calcineurin-dependent hypertrophic stimulus in tropomodulin overexpressing transgenics elevated heart:body weight ratios, increased ventricular wall thickness, and significantly accelerated mortality [3].

Analytical, diagnostic and therapeutic context of Tmod1

• The spatial and temporal expression of the Tmod gene was examined during mouse embryogenesis using in situ hybridization [10].
• The human E-Tmod gene obtained by PCR has an identical exon-intron organization [13].

References