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.
Huang
Facan
F
Department of Anatomy and Cell Biology, Center for Cardiovascular and Muscle Research, State University of New York, Health Science Center at Brooklyn, Box 5, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Wagner
Michael
M
Siddiqui
M A Q
MA
D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015152:Blotting, Northern; D024722:Cardiac Myosins / Q000096:biosynthesis; D009202:Cardiomyopathies / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D005838:Genotype; D006352:Heart Ventricles / Q000002:abnormalities / Q000196:embryology*; D006579:Heterozygote; D006720:Homozygote; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008957:Models, Genetic; D016296:Mutagenesis; D009154:Mutation; D018994:Myosin Light Chains / Q000096:biosynthesis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D019076:Transgenes; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D024722:Cardiac Myosins; D005819:Genetic Markers; D018994:Myosin Light Chains; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C095572:Hand1 protein, mouse; C498766:Hand2 protein, mouse; C118642:Hexim1 protein, mouse; C410915:hand2 protein, zebrafish; C107184:myosin light chain 2