title: Neuromuscular synapse formation in mice lacking motor neuron- and skeletal muscle-derived Neuregulin-1.
abstract: The localization of acetylcholine receptors (AChRs) to the vertebrate neuromuscular junction is mediated, in part, through selective transcription of AChR subunit genes in myofiber subsynaptic nuclei. Agrin and the muscle-specific receptor tyrosine kinase, MuSK, have critical roles in synapse-specific transcription, because AChR genes are expressed uniformly in mice lacking either agrin or MuSK. Several lines of evidence suggest that agrin and MuSK stimulate synapse-specific transcription indirectly by regulating the distribution of other cell surface ligands, which stimulate a pathway for synapse-specific gene expression. This putative secondary signal for directing AChR gene expression to synapses is not known, but Neuregulin-1 (Nrg-1), primarily based on its presence at synapses and its ability to induce AChR gene expression in vitro, has been considered a good candidate. To study the role of Nrg-1 at neuromuscular synapses, we inactivated nrg-1 in motor neurons, skeletal muscle, or both cell types, using mice that express Cre recombinase selectively in developing motor neurons or in developing skeletal myofibers. We find that AChRs are clustered at synapses and that synapse-specific transcription is normal in mice lacking Nrg-1 in motor neurons, myofibers, or both cell types. These data indicate that Nrg-1 is dispensable for clustering AChRs and activating AChR genes in subsynaptic nuclei during development and suggest that these aspects of postsynaptic differentiation are dependent on Agrin/MuSK signaling without a requirement for a secondary signal.
authors.affiliation: Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jaworski
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
mesh_terms: D018171:Agrin / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D003964:Diaphragm / Q000196:embryology / Q000294:innervation; D066246:ErbB Receptors / Q000378:metabolism; D017930:Genes, Reporter; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007366:Intercostal Muscles / Q000196:embryology / Q000294:innervation; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000196:embryology / Q000294:innervation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020890:Neuregulin-1; D009469:Neuromuscular Junction / Q000196:embryology / Q000502:physiology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D011950:Receptors, Cholinergic / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
chemical_list: D018171:Agrin; D066246:ErbB Receptors; D019426:Integrases; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011950:Receptors, Cholinergic; D014764:Viral Proteins; D001616:beta-Galactosidase; C490581:Nrg1 protein, mouse; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C095714:MUSK protein, human; C045073:Cre recombinase