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Am J Physiol Cell Physiol (June 1, 2005). doi:10.1152/ajpcell.00196.2005
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Submitted on April 26, 2005
Accepted on May 27, 2005

Calcineurin/NFAT Signaling, Together with GABP and PGC-1{alpha}, Drives Utrophin Gene Expression at the Neuromuscular Junction

Lindsay M Angus1, Joe V Chakkalakal1, Alexandre Mejat2, Joe K Eibl3, Guy Belanger1, Lynn A Megeney4, Eva R Chin5, Laurent Schaeffer2, Robin N Michel3, and Bernard J Jasmin4*

1 Cellular and Molecular Medicine and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON, Canada
2 Equipe Differentiation Neuromusculaire, Ecole Normale Superieure de Lyon, Lyon, France
3 Chemistry and Biochemistry and Neuromuscular Research Laboratory, Laurentian University, Sudbury, ON, Canada
4 Cellular and Molecular Medicine and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON, Canada; Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, ON, Canada
5 Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, San Diego, CA, USA

* To whom correspondence should be addressed. E-mail: jasmin{at}uottawa.ca.

We examined whether calcineurin/NFAT 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 versus 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 cyclosporine 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 construct. Transfection assays performed with cultured myogenic cells indicated that calcineurin acts additively with GABP to transactivate utrophin A gene expression. Since both GABP and calcineurin-mediated pathways are targeted by PGC-1{alpha}, we examined whether this co-factor contributes to utrophin gene expression. In vitro and in vivo transfection experiments showed that PGC-1{alpha} alone induces transcription from the utrophin A promoter. Interestingly, this induction is largely potentiated by co-expression of PGC-1{alpha} 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{alpha}.




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