title: Implication of a multisubunit Ets-related transcription factor in synaptic expression of the nicotinic acetylcholine receptor.
abstract: In adult muscle, transcription of the nicotinic acetylcholine receptor (AChR) is restricted to the nuclei located at the neuromuscular junction. The N-box, a new promoter element, was identified recently and shown to contribute to this compartmentalized synaptic expression of the AChR delta- and epsilon-subunits. We demonstrate that the N-box mediates transcriptional activation in cultured myotubes and identify the transcription factor that binds to the N-box as a heterooligomer in myotubes and adult muscle. The GABP (GA-binding protein) alpha-subunit belongs to the Ets family of transcription factors, whereas the beta-subunit shares homology with IkappaB and Drosophila Notch protein. GABP binding specificity to mutated N-box in vitro strictly parallels the sequence requirement for beta-galactosidase targeting to the endplate in vivo. In situ hybridization studies reveal that the mRNAs of both GABP subunits are abundant in mouse diaphragm, with preferential expression of the alpha-subunit at motor endplates. In addition, heregulin increases GABPalpha protein levels and regulates phosphorylation of both subunits in cultured chick myotubes. Finally, dominant-negative mutants of either GABPalpha or GABPbeta block heregulin-elicited transcriptional activation of the AChR delta and epsilon genes. These findings establish the expected connection with a presynaptic trophic factor whose release contributes to the accumulation of AChR subunit mRNAs at the motor endplate.
authors.affiliation: CNRS UA D 1284 'Neurobiologie Moléculaire', Institut Pasteur, 25 rue du Dr Roux, F-75724 Cedex 15, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Schaeffer
authors.forename: N
authors.initials: N
authors.lastname: Duclert
authors.forename: M
authors.initials: M
authors.lastname: Huchet-Dymanus
authors.forename: J P
authors.initials: JP
authors.lastname: Changeux
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D051268:GA-Binding Protein Transcription Factor; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008970:Molecular Weight; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020880:Neuregulins; D018733:Nicotinic Antagonists / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000235:genetics; D011978:Receptors, Nicotinic / Q000096:biosynthesis* / Q000235:genetics; D013569:Synapses / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; C495656:Gabpa protein, mouse; C495658:Gabpb1 protein, mouse; D006023:Glycoproteins; D020880:Neuregulins; D018733:Nicotinic Antagonists; D016376:Oligonucleotides, Antisense; D010455:Peptides; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D014157:Transcription Factors