Ablation of the CLP-1 gene leads to down-regulation of the HAND1 gene and abnormality of the left ventricle of the heart and fetal death
Copyright policy )Ablation of the CLP-1 gene leads to down-regulation of the HAND1 gene and abnormality of the left ventricle of the heart and fetal death
We have recently reported that cardiac lineage protein-1 (CLP-1), a nuclear protein with an acidic region that constitutes a potential protein-protein interaction domain, regulates transcription of the cardiac myosin light chain-2v (MLC-2v) gene promoter in a manner consistent with its being a transcriptional co-activator or regulator. To test the postulate that CLP-1 is a regulator of cardiac genes we ablated the CLP-1 gene in mice. Past embryonic day (E)16.5, CLP-1 null alleles did not show Mendelian inheritance suggesting that absence of CLP-1 was lethal in late fetal stages. CLP-1 (-/-) fetal hearts exhibited a reduced left ventricular chamber with thickened myocardial walls, features suggestive of cardiac hypertrophy. Electron microscopic analysis of E16.5 CLP-1 (-/-) ventricular myocardium showed a marked decline in cell density and altered nuclear and myofibril morphologies similar to that seen in animal models of hypertrophic heart. Analysis of contractile and non-contractile protein genes known to be re-expressed during cardiac hypertrophy showed them to have higher expression levels in CLP-1 (-/-) hearts thereby confirming the hypertrophic phenotype at the molecular level. Analysis of cardiac development genes showed that expression of the HAND1 transcription factor, a gene involved in patterning of the heart tube and down-regulated in hypertrophic hearts, was also significantly reduced in CLP-1 (-/-) fetal hearts. CLP-1 and HAND1 have similar expression patterns in the developing heart ventricles. These data suggest that CLP-1 and the HAND transcription factors may be part of a genetic program critical to proper heart development, perturbation of which can lead to cardiomyopathy.
- State University of New York at Potsdam United States
- State University of New York United States
Genetic Markers, Mice, Knockout, Embryology, Heterozygote, Genotype, Heart Ventricles, Homozygote, Down-Regulation, Gene Expression Regulation, Developmental, Mice, Transgenic, Blotting, Northern, Embryo, Mammalian, Mice, Microscopy, Electron, Gene Expression Regulation, Basic Helix-Loop-Helix Transcription Factors, Animals, Cardiomyopathies, Cardiac Myosins, Alleles, In Situ Hybridization, Developmental Biology
Genetic Markers, Mice, Knockout, Embryology, Heterozygote, Genotype, Heart Ventricles, Homozygote, Down-Regulation, Gene Expression Regulation, Developmental, Mice, Transgenic, Blotting, Northern, Embryo, Mammalian, Mice, Microscopy, Electron, Gene Expression Regulation, Basic Helix-Loop-Helix Transcription Factors, Animals, Cardiomyopathies, Cardiac Myosins, Alleles, In Situ Hybridization, Developmental Biology
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