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Vol. 18, Issue 5, 1723-1733, May 2007

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The Cytoskeleton-associated PDZ-LIM Protein, ALP, Acts on Serum Response Factor Activity to Regulate Muscle Differentiation

Pascal Pomiès^*,,, Mohammad Pashmforoush^,, Cristina Vegezzi^,||, Kenneth R. Chien, Charles Auffray, and Mary C. Beckerle^||

*Centre National de la Recherche Scientifique Unité Mixte de Recherche 5237, Centre de Recherches de Biochimie Macromoléculaire, 34293 Montpellier, France; Centre National de la Recherche Scientifique FRE 2571, Génomique Fonctionnelle et Biologie Systémique en Santé, 94801 Villejuif, France; University of California at San Diego (UCSD)-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California at San Diego, La Jolla, CA 92037; and ^||Department of Biology and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112

Submitted September 13, 2006; Revised January 18, 2007; Accepted February 15, 2007
Monitoring Editor: Marianne Bronner-Fraser

In this report, an antisense RNA strategy has allowed us to show that disruption of ALP expression affects the expression of the muscle transcription factors myogenin and MyoD, resulting in the inhibition of muscle differentiation. Introduction of a MyoD expression construct into ALP-antisense cells is sufficient to restore the capacity of the cells to differentiate, illustrating that ALP function occurs upstream of MyoD. It is known that MyoD is under the control of serum response factor (SRF), a transcriptional regulator whose activity is modulated by actin dynamics. A dramatic reduction of actin filament bundles is observed in ALP-antisense cells and treatment of these cells with the actin-stabilizing drug jasplakinolide stimulates SRF activity and restores the capacity of the cells to differentiate. Furthermore, we show that modulation of ALP expression influences SRF activity, the level of its coactivator, MAL, and muscle differentiation. Collectively, these results suggest a critical role of ALP on muscle differentiation, likely via cytoskeletal regulation of SRF.

These authors contributed equally to this work.

Address correspondence to: Pascal Pomiès (pascal.pomies{at}crbm.cnrs.fr)