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MBC in Press, published online ahead of print May 16, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1069

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Submitted on December 4, 2006
Revised on May 4, 2007
Accepted on May 7, 2007

ERF Silences Extrasynaptic Utrophin by N-Box-mediated Repression in Skeletal Muscle

Kelly J. Perkins,*{dagger} Utpal Basu,* Murat T. Budak,* Caroline Ketterer,* Santhosh M. Baby,* Olga Lozynska,* John A. Lunde,{ddagger} Bernard J. Jasmin,{ddagger} Neal A. Rubinstein,* and Tejvir S. Khurana*

*Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085; {ddagger}Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada

Monitoring Editor: William Tansey

Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne’s muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated ERK-phosphorylation, leading to binding of GABP{alpha}/{beta} to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extra-synaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extra-synaptic utrophin-A in muscle. Gel-shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-Box/EBS site. ERF overexpression repressed utrophin-A promoter activity: conversely, siRNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extra-synaptic transcriptomes and gene transfer studies provide spatial and direct evidence respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest "repressing repressors" as a potential strategy for achieving utrophin upregulation in DMD and provide a model for utrophin-A regulation in muscle.

{dagger}Present address: Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom.

Address correspondence to: Tejvir S. Khurana (tsk{at}mail.med.upenn.edu)




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