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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Agrin / physiology
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Animals
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Cell Differentiation
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Diaphragm / embryology
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Diaphragm / innervation
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ErbB Receptors / metabolism
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Genes, Reporter
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Integrases / genetics
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Integrases / metabolism
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Intercostal Muscles / embryology
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Intercostal Muscles / innervation
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Mice
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Mice, Knockout
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Motor Neurons / metabolism
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Motor Neurons / ultrastructure
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Muscle Fibers, Skeletal / metabolism
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Muscle Fibers, Skeletal / ultrastructure
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Muscle, Skeletal / embryology
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Muscle, Skeletal / innervation
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Neuregulin-1
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Neuromuscular Junction / embryology
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Neuromuscular Junction / physiology*
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Neuromuscular Junction / ultrastructure
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-4
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Receptors, Cholinergic / biosynthesis*
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Receptors, Cholinergic / genetics
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Receptors, Cholinergic / physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Deletion
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Viral Proteins / genetics
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Viral Proteins / metabolism
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beta-Galactosidase / analysis
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beta-Galactosidase / genetics
Substances
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Agrin
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Nerve Tissue Proteins
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Neuregulin-1
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Nrg1 protein, mouse
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RNA, Messenger
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Receptors, Cholinergic
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Viral Proteins
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ERBB4 protein, human
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ErbB Receptors
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Erbb4 protein, mouse
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MUSK protein, human
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Receptor Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Receptor, ErbB-4
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Cre recombinase
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Integrases
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beta-Galactosidase