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Molecular and Cellular Biology, June 2004, p. 5281-5289, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5281-5289.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Targeted Inactivation of Serum Response Factor in the Developing Heart Results in Myocardial Defects and Embryonic Lethality

Ara Parlakian,1,{dagger} David Tuil,2,{dagger} Ghislaine Hamard,3 Geneviève Tavernier,2 Daniele Hentzen,2 Jean-Paul Concordet,2 Denise Paulin,1,{ddagger} Zhenlin Li,1,{ddagger}* and Dominique Daegelen2,{ddagger}

Laboratoire de Biologie Moléculaire de la Différenciation, Université Paris 7, 75005 Paris,1 Département Génétique, Développement et Pathologie Moléculaire,2 Plateau de Recombinaison Homologue, Institut Cochin, INSERM U567, CNRS 5, URA 8104, Université Paris, 75014 Paris, France3

Received 15 November 2003/ Returned for modification 15 January 2004/ Accepted 20 March 2004

Serum response factor (SRF) is at the confluence of multiple signaling pathways controlling the transcription of immediate-early response genes and muscle-specific genes. There are active SRF target sequences in more than 50 genes expressed in the three muscle lineages including normal and diseased hearts. However, the role of SRF in heart formation has not been addressed in vivo thus far due to the early requirement of SRF for mesoderm formation. We have generated a conditional mutant of SRF by using Cre-LoxP strategy that will be extremely useful to study the role of SRF in embryonic and postnatal cardiac functions, as well as in other tissues. This report shows that heart-specific deletion of SRF in the embryo by using a new ßMHC-Cre transgenic mouse line results in lethal cardiac defects between embryonic day 10.5 (E10.5) and E13.5, as evidenced by abnormally thin myocardium, dilated cardiac chambers, poor trabeculation, and a disorganized interventricular septum. At E9.5, we found a marked reduction in the expression of essential regulators of heart development, including Nkx2.5, GATA4, myocardin, and the SRF target gene c-fos prior to overt maldevelopment. We conclude that SRF is crucial for cardiac differentiation and maturation, acting as a global regulator of multiple developmental genes.

* Corresponding author. Mailing address: Laboratoire de Biologie Moléculaire de la Différenciation, Université Paris 7, Case 7136, 2 Place Jussieu, 75005 Paris, France. Phone: 331-44-27-69-94. Fax: 331-44-27-36-15. E-mail: zhenli{at}ccr.jussieu.fr.

{dagger} A.P. and D.T. contributed equally to this study.

{ddagger} D.P., Z.L., and D.D. were principal investigators.

Molecular and Cellular Biology, June 2004, p. 5281-5289, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5281-5289.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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