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Annals of the New York Academy of... Feb 2018Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific... (Review)
Review
Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.
Topics: Agrin; Animals; Autoantibodies; Humans; LDL-Receptor Related Proteins; Mice; Myasthenia Gravis; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 29377176
DOI: 10.1111/nyas.13573 -
Neuroreport Aug 2002The extracellular matrix molecule agrin mediates the motor neuron induced accumulation of acetylcholine receptors (AChR) at the neuromuscular junction. Agrin is also... (Review)
Review
The extracellular matrix molecule agrin mediates the motor neuron induced accumulation of acetylcholine receptors (AChR) at the neuromuscular junction. Agrin is also present in the CNS. However, while its spatiotemporal pattern of expression is consistent with a function in neuron-neuron synapse formation, it also suggests a role for agrin in other aspects of neural tissue morphogenesis. Here we review the data supporting these synaptic and non-synaptic functions of agrin in the CNS. The results of studies aimed at identifying a neuronal receptor for agrin (NRA) and its associated signal transduction pathways are examined. Possible roles for agrin in the etiology of diseases affecting the brain are also discussed.
Topics: Agrin; Central Nervous System; Synapses
PubMed: 12218692
DOI: 10.1097/00001756-200208270-00001 -
Proceedings of the National Academy of... Jun 2023MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK...
MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK family, MuSK activation requires not only its cognate ligand agrin but also its coreceptors LRP4. However, how agrin and LRP4 coactivate MuSK remains unclear. Here, we report the cryo-EM structure of the extracellular ternary complex of agrin/LRP4/MuSK in a stoichiometry of 1:1:1. This structure reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, thereby promoting a direct interaction between agrin and MuSK. Our cryo-EM analyses therefore uncover the assembly mechanism of agrin/LRP4/MuSK signaling complex and reveal how MuSK receptor is activated by concurrent binding of agrin and LRP4.
Topics: Receptors, Cholinergic; Agrin; LDL-Receptor Related Proteins; Signal Transduction; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases
PubMed: 37252960
DOI: 10.1073/pnas.2300453120 -
Neurochemistry International Apr 1994Agrin, a molecule synthesized by motorneurons, plays a key role in the formation of the neuromuscular junction. Agrin is released from motoneurons at the axon terminal... (Review)
Review
Agrin, a molecule synthesized by motorneurons, plays a key role in the formation of the neuromuscular junction. Agrin is released from motoneurons at the axon terminal after anterograde axonal transport and binds to agrin receptors present on muscle cells. Through a tyrosine kinase-dependent signal transduction mechanism agrin induces rearrangement of various cytoskeletal, cytoplasmic and membrane proteins of muscle cells, giving rise to the molecular topography characteristic of postsynaptic membranes. The most prominent aspect of these rearrangements is the aggregation of acetylcholine receptors and acetylcholinesterases in postsynaptic membranes of muscle cells. Agrin and agrin-like proteins deposited in the extracellular matrix of the synaptic cleft may also serve as a reservoir of trophic factors for motor neurons thereby ensuring the maintenance of a long-lasting synaptic architecture.
Topics: Agrin; Amino Acid Sequence; Animals; Cell Differentiation; Molecular Sequence Data; Neuromuscular Junction; Receptors, Cholinergic; Sequence Alignment; Structure-Activity Relationship; Synaptic Membranes
PubMed: 8061595
DOI: 10.1016/0197-0186(94)90108-2 -
The International Journal of... 2007Neural agrin is a heparan sulphate proteoglycan first defined by its ability to induce the clustering of acetylcholine receptors (AChRs) on cultured muscle cells. Neural... (Review)
Review
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. Here we briefly review some key mechanisms through which neural agrin acts to foster the formation of mature neuromuscular synapses.
Topics: Agrin; Animals; Humans; Models, Biological; Neuromuscular Junction; Receptors, Cholinergic; Signal Transduction; Synapses
PubMed: 17126587
DOI: 10.1016/j.biocel.2006.10.012 -
Current Opinion in Cell Biology Oct 1992Agrin is thought to mediate the motor neuron-induced aggregation of synaptic proteins on the surface of muscle fibers at neuromuscular junctions. Recent experiments... (Review)
Review
Agrin is thought to mediate the motor neuron-induced aggregation of synaptic proteins on the surface of muscle fibers at neuromuscular junctions. Recent experiments provide direct evidence in support of this hypothesis, reveal the nature of agrin immunoreactivity at sites other than neuromuscular junctions, and have resulted in findings that are consistent with the possibility that agrin plays a role in synaptogenesis throughout the nervous system.
Topics: Agrin; Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Motor Neurons; Nerve Tissue Proteins; Synapses
PubMed: 1329871
DOI: 10.1016/0955-0674(92)90113-q -
Trends in Cancer Feb 2020Angiogenesis represents a hallmark of cancer. Several proteoglycans associate with cell surface receptors and regulate angiogenesis within the tumor microenvironment...
Angiogenesis represents a hallmark of cancer. Several proteoglycans associate with cell surface receptors and regulate angiogenesis within the tumor microenvironment (TME). We highlight the recent discovery that the proteoglycan Agrin cross talks between the tumor and the endothelium to promote an angiogenesis privileged niche during cancer progression.
Topics: Agrin; Alternative Splicing; Angiogenesis Inhibitors; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Progression; Endothelium, Vascular; Extracellular Matrix; Humans; Liver; Liver Neoplasms; Neovascularization, Pathologic; Protein Isoforms; Tumor Microenvironment
PubMed: 32061308
DOI: 10.1016/j.trecan.2019.12.002 -
Trends in Neurosciences Jan 1998The synapse is a key structure that is involved in perception, learning and memory. Understanding the sequence of steps that is involved in establishing synapses during... (Review)
Review
The synapse is a key structure that is involved in perception, learning and memory. Understanding the sequence of steps that is involved in establishing synapses during development might also help to understand mechanisms that cause changes in synapses during learning and memory. For practical reasons, most of our current knowledge of synapse development is derived from studies of the vertebrate neuromuscular junction (NMJ). Several lines of evidence strongly suggest that motor axons release the molecule agrin to induce the formation of the postsynaptic apparatus in muscle fibers. Recent advances implicate proteins such as dystroglycan, MuSK, and rapsyn in the transduction of agrin signals. Recently, additional functions of agrin have been discovered, including the upregulation of gene transcription in myonuclei and the control of presynaptic differentiation. Agrin therefore appears to play a unique role in controlling synaptic differentiation on both sides of the NMJ.
Topics: Agrin; Animals; Cell Differentiation; Humans; Neuromuscular Junction; Neurons; Synapses
PubMed: 9464682
DOI: 10.1016/s0166-2236(97)01154-5 -
Cell May 1996
Review
Topics: Agrin; Animals; Neuromuscular Junction
PubMed: 8653780
DOI: 10.1016/s0092-8674(00)81245-3 -
Journal of Cardiovascular Pharmacology Jan 2021Embryonic epicardial cells make an important contribution to cardiac development. However, their proliferation mechanism is still unclear. Epicardial cells from E12.5...
Embryonic epicardial cells make an important contribution to cardiac development. However, their proliferation mechanism is still unclear. Epicardial cells from E12.5 fetal hearts were used in our study. Agrin was used to treat these cells. The expression of Aurora B, Ki67, and pH3 was measured by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. The proportion of cells in G1/S/G2 phase was determined by flow cytometry. The results showed that agrin significantly increased the expression of ki67, pH3, and Aurora B in epicardial cells. Flow cytometry results showed that agrin significantly increased the proportion of epicardial cells in S phase. However, blocking yes-associated protein significantly downregulated the levels of ki67, pH3, and Aurora B and the proportion of epicardial cells in S phase. Thus, our results suggest that agrin may promote the proliferation of epicardial cells by regulating the yes-associated protein activity. This may be useful in exploring heart development mechanisms and preventing congenital heart disease.
Topics: Adaptor Proteins, Signal Transducing; Agrin; Animals; Aurora Kinase B; Cell Cycle; Cell Proliferation; Cells, Cultured; Female; Fetal Heart; Histones; Ki-67 Antigen; Male; Mice; Pericardium; Phosphorylation; YAP-Signaling Proteins
PubMed: 33136763
DOI: 10.1097/FJC.0000000000000926