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Molecular and Cellular Biology, December 2003, p. 9222-9232, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9222-9232.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Myocardin Expression Is Regulated by Nkx2.5, and Its Function Is Required for Cardiomyogenesis

Tomomi Ueyama, Hideko Kasahara,{dagger} Takahiro Ishiwata, Qing Nie, and Seigo Izumo*

Cardiovascular Division, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

Received 14 March 2003/ Returned for modification 5 May 2003/ Accepted 21 July 2003

Nkx2.5 (also known as Csx) is an evolutionarily conserved cardiac transcription factor of the homeobox gene family. Nkx2.5 is required for early heart development, since Nkx2.5-null mice die before completion of cardiac looping. To identify genes regulated by Nkx2.5 in the developing heart, we performed subtractive hybridization by using RNA isolated from wild-type and Nkx2.5-null hearts at embryonic day 8.5. We isolated a mouse cDNA encoding myocardin A, which is an alternative spliced isoform of myocardin and the most abundant isoform in the heart from embryo to adult. The expression of myocardin A and myocardin was markedly downregulated in Nkx2.5-null mouse hearts. Transient-cotransfection analysis showed that Nkx2.5 transactivates the myocardin promoter. Inhibition of myocardin function in the teratocarcinoma cell line P19CL6 prevented differentiation into cardiac myocytes after dimethyl sulfoxide treatment. Myocardin A transactivated the promoter of the atrial natriuretic factor gene through the serum response element, which was augmented by bone morphogenetic protein 2 and transforming growth factor ß-activated kinase 1. These results suggest that myocardin expression is regulated by Nkx2.5 and that its function is required for cardiomyogenesis.

* Corresponding author. Mailing address: Cardiovascular Division, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02215. Phone: (617) 667-4858. Fax: (617) 975-5268. E-mail: sizumo{at}caregroup.harvard.edu.

{dagger} Present address: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610-0274.

Molecular and Cellular Biology, December 2003, p. 9222-9232, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9222-9232.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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