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

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Abstract

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.

Keywords

Cardiac lineage protein-1
Gene ablation
Cardiac hypertrophy
HAND1
HAND2

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1

These authors contributed equally to this work.

2

Present Address: Cardiovascular Division, Department of Medicine, University of Pennsylvania.