PAK1 and CtBP1 Regulate the Coupling of Neuronal Activity to Muscle Chromatin and Gene Expression

Abstract

Acetylcholine receptor (AChR) expression in innervated muscle is limited to the synaptic region. Neuron-induced electrical activity participates in this compartmentalization by promoting the repression of AChR expression in the extrasynaptic regions. Here, we show that the corepressor CtBP1 (C-terminal binding protein 1) is present on the myogenin promoter together with repressive histone marks. shRNA-mediated downregulation of CtBP1 expression is sufficient to derepress myogenin and AChR expression in innervated muscle. Upon denervation, CtBP1 is displaced from the myogenin promoter and relocates to the cytoplasm, while repressive histone marks are replaced by activating ones concomitantly to the activation of myogenin expression. We also observed that upon denervation the p21-activated kinase 1 (PAK1) expression is upregulated, suggesting that phosphorylation by PAK1 may be involved in the relocation of CtBP1. Indeed, preventing CtBP1 Ser158 phosphorylation induces CtBP1 accumulation in the nuclei and abrogates the activation of myogenin and AChR expression. Altogether, these findings reveal a molecular mechanism to account for the coordinated control of chromatin modifications and muscle gene expression by presynaptic neurons via a PAK1/CtBP1 pathway.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00354-15.

ACKNOWLEDGMENTS

We are grateful to Francesca Palladino and Yann-Gaël Gangloff for critical reading of the manuscript, Véronique Morel for assistance with statistical analyses, Adeline Govehovitch for technical assistance, and Alexandre Guiraud for providing the mCherry-Nuc plasmid. We acknowledge the technical support of the animal facility (PBES) and the imaging facility (PLATIM) of SFR Biosciences.

This study was supported by ANR and AFM grants and by INSERM (V.M.). C.V. received an Italian Foundation for Cancer Research Fellowships (FIRC, Milan, Italy). This study was also supported by Italian Association for Cancer Research (AIRC, Milan, Italy) grant IG 14675 to D.C.

J.-L.T., V.M., A.R.-C., A.M., and L.S. designed and performed the experiments, C.V. and D.C. designed and generated the YFP-CtBP1 plasmid, and J.-L.T, V.M., and L.S. contributed in writing the paper.