title: Nestin negatively regulates postsynaptic differentiation of the  neuromuscular synapse.
abstract: Positive and negative regulation of neurotransmitter receptor aggregation on the postsynaptic membrane is a critical event during synapse formation. Acetylcholine (ACh) and agrin are two opposing signals that regulate ACh receptor (AChR) clustering during neuromuscular junction (NMJ) development. ACh induces dispersion of AChR clusters that are not stabilized by agrin via a cyclin-dependent kinase 5 (Cdk5)-mediated mechanism, but regulation of Cdk5 activation is poorly understood. We found that the intermediate filament protein nestin physically interacts with Cdk5 and is required for ACh-induced association of p35, the co-activator of Cdk5, with the muscle membrane. Blockade of nestin-dependent signaling inhibited ACh-induced Cdk5 activation and the dispersion of AChR clusters in cultured myotubes. Similar to the effects of Cdk5 gene inactivation, knockdown of nestin in agrin-deficient mouse embryos substantially restored AChR clusters. These results suggest that nestin is required for ACh-induced, Cdk5-dependent dispersion of AChR clusters during NMJ development.
authors.affiliation: The Salk Institute, La Jolla, California, USA.
authors.forename: Jiefei
authors.initials: J
authors.lastname: Yang
authors.forename: Bertha
authors.initials: B
authors.lastname: Dominguez
authors.forename: Fred
authors.initials: F
authors.lastname: de Winter
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gould
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.forename: Kuo-Fen
authors.initials: KF
authors.lastname: Lee
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004789:Enzyme Activation; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D064231:Nestin; D009469:Neuromuscular Junction / Q000502:physiology* / Q000648:ultrastructure*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism
chemical_list: D018171:Agrin; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011950:Receptors, Cholinergic; D051360:Cyclin-Dependent Kinase 5; D000109:Acetylcholine