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Molecular and Cellular Biology, October 1999, p. 7096-7105, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Bone Morphogenetic Proteins Induce Cardiomyocyte Differentiation through the Mitogen-Activated Protein Kinase Kinase Kinase TAK1 and Cardiac Transcription Factors Csx/Nkx-2.5 and GATA-4

Koshiro Monzen,1 Ichiro Shiojima,1 Yukio Hiroi,1 Sumiyo Kudoh,1 Toru Oka,1 Eiki Takimoto,1 Doubun Hayashi,1 Toru Hosoda,1 Akemi Habara-Ohkubo,2,dagger Takashi Nakaoka,3,Dagger Toshiro Fujita,3 Yoshio Yazaki,1,§ and Issei Komuro1,*

Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655,1 Department of Gene Regulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 862,2 and Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo 112-8688,3 Japan

Received 22 January 1999/Returned for modification 16 March 1999/Accepted 20 July 1999

Bone morphogenetic proteins (BMPs) have been shown to induce ectopic expression of cardiac transcription factors and beating cardiomyocytes in nonprecardiac mesodermal cells in chicks, suggesting that BMPs are inductive signaling molecules that participate in the development of the heart. However, the precise molecular mechanisms by which BMPs regulate cardiac development are largely unknown. In the present study, we examined the molecular mechanisms by which BMPs induce cardiac differentiation by using the P19CL6 in vitro cardiomyocyte differentiation system, a clonal derivative of P19 embryonic teratocarcinoma cells. We established a permanent P19CL6 cell line, P19CL6noggin, which constitutively overexpresses the BMP antagonist noggin. Although almost all parental P19CL6 cells differentiate into beating cardiomyocytes when treated with 1% dimethyl sulfoxide, P19CL6noggin cells did not differentiate into beating cardiomyocytes nor did they express cardiac transcription factors or contractile protein genes. The failure of differentiation was rescued by overexpression of BMP-2 or addition of BMP protein to the culture media, indicating that BMPs were indispensable for cardiomyocyte differentiation in this system. Overexpression of TAK1, a member of the mitogen-activated protein kinase kinase kinase superfamily which transduces BMP signaling, restored the ability of P19CL6noggin cells to differentiate into cardiomyocytes and concomitantly express cardiac genes, whereas overexpression of the dominant negative form of TAK1 in parental P19CL6 cells inhibited cardiomyocyte differentiation. Overexpression of both cardiac transcription factors Csx/Nkx-2.5 and GATA-4 but not of Csx/Nkx-2.5 or GATA-4 alone also induced differentiation of P19CL6noggin cells into cardiomyocytes. These results suggest that TAK1, Csx/Nkx-2.5, and GATA-4 play a pivotal role in the cardiogenic BMP signaling pathway.

* Corresponding author. Mailing address: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-3818-6672. Fax: 81-3-3818-6673. E-mail: komuro-tky{at}umin.ac.jp.

dagger Deceased on 10 October 1998.

Dagger Present address: Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425.

§ Present address: International Medical Center of Japan, Tokyo 162-8655, Japan.

Molecular and Cellular Biology, October 1999, p. 7096-7105, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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