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

Publication ,  Journal Article
Angus, LM; Chakkalakal, JV; Méjat, A; Eibl, JK; Bélanger, G; Megeney, LA; Chin, ER; Schaeffer, L; Michel, RN; Jasmin, BJ
Published in: Am J Physiol Cell Physiol
October 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-gamma coactivator-1alpha (PGC-1alpha), we examined whether this coactivator contributes to utrophin gene expression. In vitro and in vivo transfection experiments showed that PGC-1alpha alone induces transcription from the utrophin A promoter. Interestingly, this induction is largely potentiated by coexpression of PGC-1alpha 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-1alpha.

Duke Scholars

Published In

Am J Physiol Cell Physiol

DOI

ISSN

0363-6143

Publication Date

October 2005

Volume

289

Issue

4

Start / End Page

C908 / C917

Location

United States

Related Subject Headings

  • Utrophin
  • Transcription Factors
  • Trans-Activators
  • Tacrolimus
  • Signal Transduction
  • Physiology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Nuclear Proteins
  • Neuromuscular Junction
  • NFATC Transcription Factors
 

Citation

APA
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MLA
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Angus, L. M., Chakkalakal, J. V., Méjat, A., Eibl, J. K., Bélanger, G., Megeney, L. A., … Jasmin, B. J. (2005). Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction. Am J Physiol Cell Physiol, 289(4), C908–C917. https://doi.org/10.1152/ajpcell.00196.2005
Angus, Lindsay M., Joe V. Chakkalakal, Alexandre Méjat, Joe K. Eibl, Guy Bélanger, Lynn A. Megeney, Eva R. Chin, Laurent Schaeffer, Robin N. Michel, and Bernard J. Jasmin. “Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction.Am J Physiol Cell Physiol 289, no. 4 (October 2005): C908–17. https://doi.org/10.1152/ajpcell.00196.2005.
Angus LM, Chakkalakal JV, Méjat A, Eibl JK, Bélanger G, Megeney LA, et al. Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction. Am J Physiol Cell Physiol. 2005 Oct;289(4):C908–17.
Angus, Lindsay M., et al. “Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction.Am J Physiol Cell Physiol, vol. 289, no. 4, Oct. 2005, pp. C908–17. Pubmed, doi:10.1152/ajpcell.00196.2005.
Angus LM, Chakkalakal JV, Méjat A, Eibl JK, Bélanger G, Megeney LA, Chin ER, Schaeffer L, Michel RN, Jasmin BJ. Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction. Am J Physiol Cell Physiol. 2005 Oct;289(4):C908–C917.

Published In

Am J Physiol Cell Physiol

DOI

ISSN

0363-6143

Publication Date

October 2005

Volume

289

Issue

4

Start / End Page

C908 / C917

Location

United States

Related Subject Headings

  • Utrophin
  • Transcription Factors
  • Trans-Activators
  • Tacrolimus
  • Signal Transduction
  • Physiology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Nuclear Proteins
  • Neuromuscular Junction
  • NFATC Transcription Factors