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J. Biol. Chem., Vol. 280, Issue 37, 32531-32538, September 16, 2005

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Conditional Mutagenesis of the Murine Serum Response Factor Gene Blocks Cardiogenesis and the Transcription of Downstream Gene Targets^*

Zhiyv Niu, Wei Yu, Shu Xing Zhang¶, Matthew Barron¶, Narasimhaswamy S. Belaguli||, Michael D. Schneider||, Michael Parmacek**, Alfred Nordheim, and Robert J. Schwartz¶1

From the Center for Cardiovascular Development, Division of Cardiovascular Sciences, Departments of Molecular and Cellular Biology, ^¶Medicine, and ^||Surgery, Baylor College of Medicine, Houston, Texas, 77030, ^**Division of Cardiovascular Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, Institute of Cell Biology, Department of Molecular Biology, Tuebingen University, D-72704 Tuebingen, Germany, and the Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030

Serum response factor (SRF) homozygous-null embryos from our backcross of SRF^LacZ/+ "knock-in" mice failed to gastrulate and form mesoderm, similar to the findings of an earlier study (Arsenian, S., Weinhold, B., Oelgeschlager, M., Ruther, U., and Nordheim, A. (1998) EMBO J. 17, 6289–6299). Our use of embryonic stem cells provided a model system that could be used to investigate the specification of multiple embryonic lineages, including cardiac myocytes. We observed the absence of myogenic -actins, SM22, and myocardin expression and the failure to form beating cardiac myocytes in aggregated SRF null embryonic stem cells, whereas the appearance of transcription factors Nkx2–5 and GATA4 were unaffected. To study the role of SRF during heart organogenesis, we then performed cardiac-specific ablation of SRF by crossing the transgenic -myosin heavy chain Cre recombinase line with SRF LoxP-engineered mice. Cardiac-specific ablation of SRF resulted in embryonic lethality due to cardiac insufficiency during chamber maturation. Conditional ablation of SRF also reduced cell survival concomitant with increased apoptosis and reduced cellularity. Significant reductions in SRF (95%), atrial naturetic factor (80%), and cardiac (60%), skeletal (90%), and smooth muscle (75%) -actin transcripts were also observed in the cardiac-conditional knock-out heart. This was consistent with the idea that SRF directs de novo cardiac and smooth muscle gene activities. Finally, quantitation of the knock-in LacZ reporter gene transcripts in the hearts of cardiac-conditional knock-out embryos revealed an 30% reduction in gene activity, indicating SRF gene autoregulation during cardiogenesis.

Received for publication, February 4, 2005 , and in revised form, May 18, 2005.

^* This project was supported by Grants P01 HL49953 and R01HL79628-01 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030. Tel.: 713-677-7710; Fax: 713-677-7784; E-mail: rschwartz{at}ibt.tamhsc.edu.

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