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Originally published In Press as doi:10.1074/jbc.M010983200 on February 5, 2001

J. Biol. Chem., Vol. 276, Issue 20, 17206-17212, May 18, 2001
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Muscle Specificity Encoded by Specific Serum Response Factor-binding Sites*

Priscilla S. ChangDagger §, Li LiDagger , John McAnallyDagger , and Eric N. OlsonDagger ||

From the Dagger  Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-9148 and  Wayne State University School of Medicine, Detroit, Michigan 48201

Serum response factor (SRF) is a MADS box transcription factor that regulates muscle-specific and growth factor-inducible genes by binding the consensus sequence CC(A/T)6GG, known as a CArG box. Because SRF expression is not restricted solely to muscle, its expression alone cannot account for the muscle specificity of some of its target genes. To understand further the role of SRF in muscle-specific transcription, we created transgenic mice harboring lacZ transgenes linked to tandem copies of different CArG boxes with flanking sequences. CArG boxes from the SM22 and skeletal alpha -actin promoters directed highly restricted expression in developing smooth, cardiac, and skeletal muscle cells during early embryogenesis. In contrast, the CArG box and flanking sequences from the c-fos promoter directed expression throughout the embryo, with no preference for muscle cells. Systematic swapping of the core and flanking sequences of the SM22 and c-fos CArG boxes revealed that cell type specificity was dictated in large part by sequences immediately flanking the CArG box core. Sequences that directed widespread embryonic expression bound SRF more strongly than those that directed muscle-restricted expression. We conclude that sequence variations among CArG boxes influence cell type specificity of expression and account, at least in part, for the ability of SRF to distinguish between growth factor-inducible and muscle-specific genes in vivo.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a Medical Science Training Program grant from the National Institutes of Health.

|| Supported by grants from the National Institutes of Health and the American Heart Association. To whom correspondence should be addressed: Dept. of Molecular Biology, University of Texas, Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9148. Tel.: 214-648-1187; Fax: 214-648-1196; E-mail: eolson@hamon.swmed.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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