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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1, drives utrophin gene expression at the neuromuscular junction

¹Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; ²Equipe Différenciation Neuromusculaire, Unité Mixte de Recherche 5161, Centre National de la Recherche Scientifique/Ecole Normale Supérieure de Lyon, Lyon, France; ³Neuromuscular Research Laboratory, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada; ⁴Molecular Medicine Program, Ottawa Health Research Institute, Ottawa Hospital, Ottawa, Ontario, Canada; ⁵Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, San Diego, California

Submitted 26 April 2005 ; accepted in final form 27 May 2005

We examined whether calcineurin-NFAT (nuclear factors of activated T cells) signaling plays a role in specifically directing the expression of utrophin in the synaptic compartment of muscle fibers. Immunofluorescence experiments revealed the accumulation of components of the calcineurin-NFAT signaling cascade within the postsynaptic membrane domain of the neuromuscular junction. RT-PCR analysis using synaptic vs. extrasynaptic regions of muscle fibers confirmed these findings by showing an accumulation of calcineurin transcripts within the synaptic compartment. We also examined the effect of calcineurin on utrophin gene expression. Pharmacological inhibition of calcineurin in mice with either cyclosporin A or FK506 resulted in a marked decrease in utrophin A expression at synaptic sites, whereas constitutive activation of calcineurin had the opposite effect. Mutation of the previously identified NFAT binding site in the utrophin A promoter region, followed by direct gene transfer studies in mouse muscle, led to an inhibition in the synaptic expression of a lacZ reporter gene construct. Transfection assays performed with cultured myogenic cells indicated that calcineurin acted additively with GA binding protein (GABP) to transactivate utrophin A gene expression. Because both GABP- and calcineurin-mediated pathways are targeted by peroxisome proliferator-activated receptor- coactivator-1 (PGC-1), we examined whether this coactivator contributes to utrophin gene expression. In vitro and in vivo transfection experiments showed that PGC-1 alone induces transcription from the utrophin A promoter. Interestingly, this induction is largely potentiated by coexpression of PGC-1 with GABP. Together, these studies indicate that the synaptic expression of utrophin is also driven by calcineurin-NFAT signaling and occurs in conjunction with signaling events that involve GABP and PGC-1.

synaptic gene expression; Duchenne muscular dystrophy; nuclear respiratory factor 2

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