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Published online on June 25, 2007, 10.1073/pnas.0611299104
PNAS | July 3, 2007 | vol. 104 | no. 27 | 11310-11315


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BIOLOGICAL SCIENCES / DEVELOPMENTAL BIOLOGY
Six proteins regulate the activation of Myf5 expression in embryonic mouse limbs

Julien Giordani*, Lola Bajard{dagger}, Josiane Demignon*, Philippe Daubas{dagger}, Margaret Buckingham{dagger}, and Pascal Maire*,{ddagger}

*Département de Génétique et Développement, Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, and Institut National de la Santé et de la Recherche Médicale, Unité 567, 75014 Paris, France; and {dagger}Département de Biologie du Développement, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2578, 25, Rue du Docteur Roux, 75015 Paris, France

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved May 24, 2007 (received for review December 19, 2006)

Myf5, a member of the myogenic regulatory factor family, plays a major role in determining myogenic cell fate at the onset of skeletal muscle formation in the embryo. Spatiotemporal control of its expression during development requires multiple enhancer elements spread over >100 kb at the Myf5 locus. Transcription in embryonic limbs is regulated by a 145-bp element located at –57.5 kb from the Myf5 gene. In the present study we show that Myf5 expression is severely impaired in the limb buds of Six1–/– and Six1–/–Six4–/+ mouse mutants despite the presence of myogenic progenitor cells. The 145-bp regulatory element contains a sequence that binds Six1 and Six4 in electromobility shift assays in vitro and in chromatin immunoprecipitation assays with embryonic extracts. We further show that Six1 is able to transactivate a reporter gene under the control of this sequence. In vivo functionality of the Six binding site is demonstrated by transgenic analysis. Mutation of this site impairs reporter gene expression in the limbs and in mature somites where the 145-bp regulatory element is also active. Six1/4 therefore regulate Myf5 transcription, together with Pax3, which was previously shown to be required for the activity of the 145-bp element. Six homeoproteins, which also directly regulate the myogenic differentiation gene Myogenin and lie genetically upstream of Pax3, thus control hypaxial myogenesis at multiple levels.

embryonic mouse limb muscle | Pax3 | Six1

Author contributions: J.G. and L.B. contributed equally to this work; J.G., L.B., P.D., M.B., and P.M. designed research; J.G., L.B., J.D., and P.D. performed research; J.G., L.B., J.D., P.D., M.B., and P.M. analyzed data; and J.G., M.B., and P.M. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0611299104/DC1.

{ddagger}To whom correspondence should be addressed at: Département de Génétique et Développement, Institut Cochin, 24, Rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: maire{at}cochin.inserm.fr

© 2007 by The National Academy of Sciences of the USA


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[Abstract] [Full Text] [PDF]