32 results match your criteria agrin-musk signaling


Agrin Influences Botulinum Neurotoxin A-Induced Nerve Sprouting via miR-144-agrin-MuSK Signaling.

Front Cell Dev Biol 2020 30;8:15. Epub 2020 Jan 30.

Neurotoxin Research Center, Tongji University School of Medicine, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education of the People's Republic of China, Shanghai, China.

Botulinum neurotoxin (BoNT) has become a powerful therapeutic tool, and is extensively used in aesthetic medicine and in the treatment of neurological disorders. However, its duration of effect is limited, mainly owing to nerve sprouting. Inhibition of nerve sprouting to prolong the effective duration of BoNT is therefore of great clinical interest. Read More

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January 2020

Crosslinking-induced endocytosis of acetylcholine receptors by quantum dots.

PLoS One 2014 25;9(2):e90187. Epub 2014 Feb 25.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.

In a majority of patients with myasthenia gravis (MG), anti-acetylcholine receptor (AChR) antibodies target postsynaptic AChR clusters and thus compromise the membrane integrity of neuromuscular junctions (NMJs) and lead to muscle weakness. Antibody-induced endocytosis of AChRs in the postsynaptic membrane represents the initial step in the pathogenesis of MG; however, the molecular mechanisms underlying AChR endocytosis remain largely unknown. Here, we developed an approach to mimic the pathogenic antibodies for inducing the crosslinking and internalization of AChRs from the postsynaptic membrane. Read More

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October 2014

Dual roles for Wnt signalling during the formation of the vertebrate neuromuscular junction.

Acta Physiol (Oxf) 2012 Jan 7;204(1):128-36. Epub 2011 May 7.

Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Chile.

Wnt proteins play prominent roles in different aspects of neuronal development culminating with the formation of complex neuronal circuits. Here, we discuss new studies addressing the function of Wnt signalling at the peripheral neuromuscular junction (NMJ). In both, invertebrate and vertebrate organisms, Wnt signalling promotes and also inhibits the assembly of the neuromuscular synapse. Read More

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January 2012

Agrin triggers the clustering of raft-associated acetylcholine receptors through actin cytoskeleton reorganization.

Biol Cell 2011 Jun;103(6):287-301

Cell Biology Program, Institut Jacques Monod, UMR 7592, CNRS/Université Paris 7-Denis Diderot, Bâtiment Buffon, 15 rue Hélène Brion, 75205 Paris Cedex 13, France.

Background Information: Cholesterol/sphingolipid-rich membrane microdomains or membrane rafts have been implicated in various aspects of receptor function such as activation, trafficking and synapse localization. More specifically in muscle, membrane rafts are involved in AChR (acetylcholine receptor) clustering triggered by the neural factor agrin, a mechanism considered integral to NMJ (neuromuscular junction) formation. In addition, actin polymerization is required for the formation and stabilization of AChR clusters in muscle fibres. Read More

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Identification of Erbin interlinking MuSK and ErbB2 and its impact on acetylcholine receptor aggregation at the neuromuscular junction.

J Neurosci 2010 May;30(19):6620-34

Institut für Biochemie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.

Erbin, a binding partner of ErbB2, was identified as the first member of the LAP family of proteins. Erbin was shown at postsynaptic membranes of the neuromuscular junction (NMJ) or in cultured C2C12 myotubes (1) to be concentrated, (2) to regulate the Ras-Raf-Mek pathway, and (3) to inhibit TGF-beta signaling. In the CNS, Erbin interacts with PSD-95. Read More

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The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction.

PLoS One 2009 Dec 29;4(12):e8478. Epub 2009 Dec 29.

Department of Biology, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.

Background: Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.

Methodology/principal Findings: In this study we used biochemical, cell biological and molecular assays to investigate a possible role in AChR clustering of cortactin, a protein which is a tyrosine kinase substrate and a regulator of F-actin assembly and which has also been previously localized at AChR clustering sites. Read More

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December 2009

New dogs in the dogma: Lrp4 and Tid1 in neuromuscular synapse formation.

Neuron 2008 Nov;60(4):526-8

Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6074, USA.

Two recent papers reported identification of a long-sought agrin coreceptor, Lrp4 (Kim et al. in Cell and Zhang et al. in Neuron). Read More

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November 2008

Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice.

Proc Natl Acad Sci U S A 2008 Aug 6;105(32):11406-11. Epub 2008 Aug 6.

Biozentrum and Institute of Physiology, Department of Biomedicine, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.

Agrin and its receptor MuSK are required for the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). In the current model the local deposition of agrin by the nerve and the resulting local activation of MuSK are responsible for creating and maintaining the postsynaptic apparatus including clusters of acetylcholine receptors (AChRs). Concomitantly, the release of acetylcholine (ACh) and the resulting depolarization disperses those postsynaptic structures that are not apposed by the nerve and thus not stabilized by agrin-MuSK signaling. Read More

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Muscle-specific receptor tyrosine kinase endocytosis in acetylcholine receptor clustering in response to agrin.

J Neurosci 2008 Feb;28(7):1688-96

Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.

Agrin, a factor used by motoneurons to direct acetylcholine receptor (AChR) clustering at the neuromuscular junction, initiates signal transduction by activating the muscle-specific receptor tyrosine kinase (MuSK). However, the underlying mechanisms remain poorly defined. Here, we demonstrated that MuSK became rapidly internalized in response to agrin, which appeared to be required for induced AChR clustering. Read More

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February 2008

Regulation of ACh receptor clustering by the tyrosine phosphatase Shp2.

Dev Neurobiol 2007 Nov;67(13):1789-801

Department of Biology, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

At the vertebrate neuromuscular junction (NMJ), postsynaptic aggregation of muscle acetylcholine receptors (AChRs) depends on the activation of MuSK, a muscle-specific tyrosine kinase that is stimulated by neural agrin and regulated by muscle-intrinsic tyrosine kinases and phosphatases. We recently reported that Shp2, a tyrosine phosphatase containing src homology two domains, suppressed MuSK-dependent AChR clustering in cultured myotubes, but how this effect of Shp2 is controlled has remained unclear. In this study, biochemical assays showed that agrin-treatment of C2 mouse myotubes enhanced the tyrosine phosphorylation of signal regulatory protein alpha1 (SIRPalpha1), a known activator of Shp2, and promoted SIRPalpha1's interaction with Shp2. Read More

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November 2007

Tyrosine phosphatases such as SHP-2 act in a balance with Src-family kinases in stabilization of postsynaptic clusters of acetylcholine receptors.

BMC Neurosci 2007 Jul 2;8:46. Epub 2007 Jul 2.

Brain Research Institute, University of Zurich, Zurich, Switzerland.

Background: Development of neural networks requires that synapses are formed, eliminated and stabilized. At the neuromuscular junction (NMJ), agrin/MuSK signaling, by triggering downstream pathways, causes clustering and phosphorylation of postsynaptic acetylcholine receptors (AChRs). Postnatally, AChR aggregates are stabilized by molecular pathways that are poorly characterized. Read More

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A role for acetylcholine receptors in their own aggregation on muscle cells.

Dev Neurobiol 2007 Jul;67(8):999-1008

Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center, Tucson, Arizona 85724-5044, USA.

Both neurotrophic factors and activity regulate synaptogenesis. At neuromuscular synapses, the neural factor agrin released from motor neuron terminals stimulates postsynaptic specialization by way of the muscle specific kinase MuSK. In addition, activity through acetylcholine receptors (AChRs) has been implicated in the stabilization of pre- and postsynaptic contacts on muscle at various stages of development. Read More

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L-type calcium channels mediate acetylcholine receptor aggregation on cultured muscle.

Dev Neurobiol 2007 Jul;67(8):987-98

Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center, Tucson, Arizona 85724-5044, USA.

Agrin activation of muscle specific kinase (MuSK) initiates postsynaptic development on skeletal muscle that includes the aggregation of acetylcholine receptors (AChRs; Glass et al. [1996]: Cell 85: 513-523; Gautam et al. [1996]: Cell 85: 525-535). Read More

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Phosphoinositide 3-kinase acts through RAC and Cdc42 during agrin-induced acetylcholine receptor clustering.

Dev Neurobiol 2007 Jul;67(8):1047-58

Center for Brain Research, Medical University of Vienna, Vienna, Austria.

The formation of the neuromuscular junction (NMJ) is regulated by the nerve-derived heparan sulfate proteoglycan agrin and the muscle-specific kinase MuSK. Agrin induces a signal transduction pathway via MuSK, which promotes the reorganization of the postsynaptic muscle membrane. Activation of MuSK leads to the phosphorylation and redistribution of acetylcholine receptors (AChRs) and other postsynaptic proteins to synaptic sites. Read More

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Differential requirement for MuSK and dystroglycan in generating patterns of neuromuscular innervation.

Proc Natl Acad Sci U S A 2007 Feb 6;104(7):2483-8. Epub 2007 Feb 6.

Department of Cell, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6058, USA.

Vertebrates display diverse patterns of neuromuscular innervation, but little is known about how such diversity is generated. In mammals, neuromuscular junctions form predominantly at equatorial locations, giving rise to a focal innervation pattern along a central endplate band. In addition, vertebrate striated muscles exhibit two nonfocal neuromuscular patterns, myoseptal and distributed innervation. Read More

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February 2007

MuSK signaling at the neuromuscular junction.

J Mol Neurosci 2006 ;30(1-2):223-6

Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, Medical College of Georgia, Augusta, GA, USA.

The neuromuscular junction (NMJ) is a peripheral cholinergic synapse that conveys signals from motor neurons to muscle cells (Sanes and Lichtman, 1999; Sanes and Lichtman, 2001). The formation of the NMJ requires communication between motoneurons and muscle fibers. Three molecules are essential for NMJ formation: agrin, MuSK, and rapsyn. Read More

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February 2007

Neural agrin: a synaptic stabiliser.

Int J Biochem Cell Biol 2007 25;39(5):863-7. Epub 2006 Oct 25.

Synaptic Biology Group, School of Biomedical Sciences (Physiology), University of Queensland, St. Lucia, Queensland, Australia.

Neural agrin is a heparan sulphate proteoglycan first defined by its ability to induce the clustering of acetylcholine receptors (AChRs) on cultured muscle cells. Neural agrin activates the transmembrane Muscle Specific Kinase (MuSK) on the postsynaptic muscle cell to stabilise the developing neuromuscular synapse. Three biological mechanisms for agrin/MuSK signalling are briefly discussed: selective transcription of synaptic genes such as MuSK itself, to reinforce developing postsynaptic clusters of AChRs; initiation of second messenger signalling pathways that can induce the formation of AChR clusters and retrograde signalling downstream of agrin/MuSK that may transform the growth cone of the motor axon into a stable differentiated nerve terminal, specialised for regulated exocytosis of neurotransmitter. Read More

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Identification of developmentally regulated expression of MuSK in astrocytes of the rodent retina.

J Neurochem 2006 Oct 8;99(2):450-7. Epub 2006 Aug 8.

Institut für Biochemie, Universität Erlangen-Nürnberg, Erlangen, Germany.

One of the master regulators of postsynaptic neuromuscular synaptogenesis is the muscle-specific receptor tyrosine kinase (MuSK). In mammals prominent MuSK expression is believed to be restricted to skeletal muscle. Upon activation by nerve-derived agrin MuSK-dependent signalling participates in both the induction of genes encoding postsynaptic components and aggregation of nicotinic acetylcholine receptors (AChR) in the subsynaptic muscle membrane. Read More

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October 2006

[The role of protein tyrosine phosphatases Shp-2 involved in the formation of the neuromuscular junction].

Zhonghua Yi Xue Za Zhi 2006 Apr;86(15):1052-6

Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China.

Objective: To investigate the involvement of protein tyrosine phosphatases Shp-2 in regulating postsynaptic signaling at the NMJ.

Methods: Cultured C2 mouse myotubes were used to mimic NMJ formation; immunoprecipitation, immuno-blot, RNA interference and immunofluorescent labeling were used in this study.

Results: We first showed that the general tyrosine phosphatase inhibitor pervanadate functionally activated MuSK and enhanced both agrin-independent and agrin-dependent AChR clustering in muscle cells: the MuSK band at 115 kD showed increased tyrosine phosphorylation after pervanadate treatment; 10 micromol/L pervanadate increased AChR clustering (mean = 6. Read More

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Lipid rafts serve as a signaling platform for nicotinic acetylcholine receptor clustering.

J Neurosci 2006 May;26(18):4841-51

Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912, USA.

Agrin, a motoneuron-derived factor, and the muscle-specific receptor tyrosine kinase (MuSK) are essential for the acetylcholine receptor (AChR) clustering at the postjunctional membrane. However, the underlying signaling mechanisms remain poorly defined. We show that agrin stimulates a dynamic translocation of the AChR into lipid rafts-cholesterol and sphingolipid-rich microdomains in the plasma membrane. Read More

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Neuromuscular synapse formation in mice lacking motor neuron- and skeletal muscle-derived Neuregulin-1.

J Neurosci 2006 Jan;26(2):655-61

Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.

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. Read More

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January 2006

Motor neurite outgrowth is selectively inhibited by cell surface MuSK and agrin.

Mol Cell Neurosci 2005 Feb;28(2):292-302

Neuroscience Program, University of Miami School of Medicine, Miami, FL 33136, USA.

During neuromuscular development, "stop signals" present on the target myotube inhibit motor axon growth. Mice lacking either the neuronal form of agrin or the muscle-specific tyrosine kinase (MuSK) lose stop signal activity, suggesting that they are part of such signals or induce them in myotubes. To test whether MuSK complexes form stop signals in the absence of myotube signaling, we cultured ciliary ganglion (CG) neurons with nonmuscle cells expressing cell-surface MuSK. Read More

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February 2005

Nitric oxide synthase activity is required for postsynaptic differentiation of the embryonic neuromuscular junction.

Dev Biol 2004 Sep;273(2):276-84

Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23501, USA.

Agrin, a synapse-organizing protein externalized by motor axons at the neuromuscular junction (NMJ), initiates a signaling cascade in muscle cells leading to aggregation of postsynaptic proteins, including acetylcholine receptors (AChRs). We examined whether nitric oxide synthase (NOS) activity is required for agrin-induced aggregation of postsynaptic AChRs at the embryonic NMJ in vivo and in cultured muscle cells. Inhibition of NOS reduced AChR aggregation at embryonic Xenopus NMJs by 50-90%, whereas overexpression of NOS increased AChR aggregate area 2- to 3-fold at these synapses. Read More

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September 2004

Neuregulin inhibits acetylcholine receptor aggregation in myotubes.

J Biol Chem 2004 Jul 20;279(30):31622-8. Epub 2004 May 20.

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

The high local concentration of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction results from their aggregation by the agrin/MuSK signaling pathway and their synthetic up-regulation by the neuregulin/ErbB pathway. Here, we show a novel role for the neuregulin/ErbB pathway, the inhibition of AChR aggregation on the muscle surface. Treatment of C2C12 myotubes with the neuregulin epidermal growth factor domain decreased the number of both spontaneous and agrin-induced AChR clusters, in part by increasing the rate of cluster disassembly. Read More

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Calcium-dependent maintenance of agrin-induced postsynaptic specializations.

Neuroscience 2003 ;122(3):659-68

Department of Neuroscience, Brown University, Box 1953, 190 Thayer Street, Providence, RI 02912, USA.

Although much progress has been made in understanding synapse formation, little is known about the mechanisms underlying synaptic maintenance and loss. The formation of agrin-induced AChR clusters on cultured myotubes requires both activation of the receptor tyrosine kinase MuSK and intracellular calcium fluxes. Here, we provide evidence that such AChR clusters are maintained by agrin/MuSK-induced intracellular calcium fluxes. Read More

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February 2004

Implication of geranylgeranyltransferase I in synapse formation.

Neuron 2003 Nov;40(4):703-17

Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Agrin activates the transmembrane tyrosine kinase MuSK to mediate acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ). However, the intracellular signaling mechanism downstream of MuSK is poorly characterized. This study provides evidence that geranylgeranyltransferase I (GGT) is an important signaling component in the Agrin/MuSK pathway. Read More

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November 2003

Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1.

Neuron 2002 Aug;35(3):489-505

Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, 1530 Third Avenue South, Birmingham, AL 35294, USA.

An important aspect of synapse development is the clustering of neurotransmitter receptors in the postsynaptic membrane. Although MuSK is required for acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ), the underlying molecular mechanisms remain unclear. We report here that in muscle cells, MuSK interacts with Dishevelled (Dvl), a signaling molecule important for planar cell polarity. Read More

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Src-class kinases act within the agrin/MuSK pathway to regulate acetylcholine receptor phosphorylation, cytoskeletal anchoring, and clustering.

J Neurosci 2001 Jun;21(11):3806-18

Department of Neuroscience, Georgetown University Medical Center, Washington DC 20007-2197, USA.

Synaptogenesis at the neuromuscular junction requires agrin-induced stable localization of acetylcholine receptors (AChRs) at the endplate. The effects of agrin are transduced by the muscle-specific receptor tyrosine kinase (MuSK). This study provides evidence that Src-class protein tyrosine kinases mediate the effects of agrin-activated MuSK to regulate clustering and anchoring of AChRs in skeletal muscle. Read More

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The Agrin/MuSK signaling pathway is spatially segregated from the neuregulin/ErbB receptor signaling pathway at the neuromuscular junction.

J Neurosci 2000 Dec;20(23):8762-70

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

The neuregulin/erbB receptor and agrin/MuSK pathways are critical for communication between the nerve, muscle, and Schwann cell that establishes the precise topological arrangement at the vertebrate neuromuscular junction (NMJ). ErbB2, erbB3, and erbB4 as well as neuregulin, agrin, and MuSK are known to be concentrated at the NMJ. Here we have examined NMJs from gastrocnemius muscle of adult rat using immunofluorescence confocal microscopy to characterize in detail the distribution of these proteins relative to the distribution of acetylcholine receptors (AChRs). Read More

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December 2000