title: 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.
authors.affiliation: Université de Lyon 1 and Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, Lyon, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Université de Lyon 1 and Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, Lyon, France vincent.moncollin@ens-lyon.fr laurent.schaeffer@univ-lyon1.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Moncollin
authors.affiliation: Université de Lyon 1 and Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, Lyon, France.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Ravel-Chapuis
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Valente
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Corda
authors.affiliation: Université de Lyon 1 and Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Méjat
authors.affiliation: Université de Lyon 1 and Laboratoire de Biologie Moléculaire de la Cellule, ENS Lyon, Lyon, France Hospices Civils de Lyon, Service d'Anatomie et Cytologie Pathologiques, Hôpital Édouard Herriot, Lyon, France vincent.moncollin@ens-lyon.fr laurent.schaeffer@univ-lyon1.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation* / Q000378:metabolism; D018008:Myogenin / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D018008:Myogenin; D034741:RNA, Small Interfering; D011950:Receptors, Cholinergic; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases