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Trends in Neurosciences Feb 1993High concentrations of neurotransmitter receptors characterize neuromuscular junctions as well as neuron-neuron synapses in the brain and periphery. Synaptic function is... (Comparative Study)
Comparative Study Review
High concentrations of neurotransmitter receptors characterize neuromuscular junctions as well as neuron-neuron synapses in the brain and periphery. Synaptic function is critically dependent upon this marshalling of neurotransmitter receptors to the post-synaptic membrane. This review discusses agrin's role in orchestrating the molecular topography of the post-synaptic apparatus at nerve-muscle synapses and the emerging evidence suggesting a role for agrin in synaptogenesis in the brain.
Topics: Agrin; Animals; Brain Chemistry; Chickens; Extracellular Matrix Proteins; Genes; Nerve Tissue Proteins; RNA Splicing; Rats; Receptor Aggregation; Receptors, Growth Factor; Receptors, Neurotransmitter; Synapses; Torpedo
PubMed: 7680503
DOI: 10.1016/0166-2236(93)90020-m -
Trends in Neurosciences Nov 1994A major effort of the past decade for those studying synaptic development has been to identify the molecular signals whose carefully choreographed exchange between pre-... (Review)
Review
A major effort of the past decade for those studying synaptic development has been to identify the molecular signals whose carefully choreographed exchange between pre- and postsynaptic cells regulates the local differentiation of each cell to form the mature synapse. Now that several of these factors [agrin, ACh-receptor inducing activity (ARIA) and calcitonin gene-related peptide] have been identified and isolated, efforts have moved toward understanding their receptors and the intracellular signaling pathways by which the factors achieve their effects. One of the most intensively studied of the synaptic signaling molecules is agrin, a large protein synthesized and released by motor neurons that induces ACh receptors and other synaptic molecules in muscle cells to accumulate at the sites of nerve contact. Recent efforts to discover the agrin receptor have led to a surprising conclusion: the only agrin-binding component so far detected in muscle cells is dystroglycan, an extracellular protein that is part of the complex of proteins associated with dystrophin, and its homologue, utrophin. Because dystroglycan binds laminin, and dystrophin binds actin, the complex containing these two proteins is thought to link the extracellular matrix to the cytoskeleton. Those interested in synapses are now pondering whether dystroglycan has a new and unexpected role as a signaling receptor for agrin-induced ACh-receptor clustering, whether it serves as an auxiliary for another receptor, or whether it serves as a receptor for an entirely different agrin-mediated function.
Topics: Agrin; Animals; Cytoskeletal Proteins; Dystroglycans; Dystrophin; Humans; Membrane Glycoproteins; Synapses
PubMed: 7531888
DOI: 10.1016/0166-2236(94)90135-x -
Muscle & Nerve Jan 2002The increasing understanding of the structural complexity of the neuromuscular junction (NMJ), and the processes that are important in its development, suggests many... (Review)
Review
The increasing understanding of the structural complexity of the neuromuscular junction (NMJ), and the processes that are important in its development, suggests many possible new disease targets. Here, we summarize briefly the genetic and autoimmune disorders that affect neuromuscular transmission, and the identified targets, including new evidence that antibodies to muscle-specific receptor tyrosine kinase (MuSK) are involved in the pathogenesis of acetylcholine receptor (AChR) antibody-negative myasthenia gravis. We then review the development of the NMJ, focusing on the important roles of nerve-derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ.
Topics: Agrin; Animals; Autoimmune Diseases; Genetic Diseases, Inborn; Humans; Neuromuscular Diseases; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 11754179
DOI: 10.1002/mus.1218 -
Cellular and Molecular Life Sciences :... Sep 2013The neuromuscular junction (NMJ) is the most extensively studied model of neuronal synaptogenesis. Acetylcholine receptor (AChR) clustering on the postsynaptic membrane... (Review)
Review
The neuromuscular junction (NMJ) is the most extensively studied model of neuronal synaptogenesis. Acetylcholine receptor (AChR) clustering on the postsynaptic membrane is a cardinal event in the differentiation of NMJs. AChR clustering and postsynaptic differentiation is orchestrated by sophisticated interactions among three proteins: the neuron-secreted proteoglycan agrin, the co-receptor LRP4, and the muscle-specific receptor tyrosine kinase MuSK. LRP4 and MuSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for AChR clustering. In this review, we discuss the structural basis for NMJ postsynaptic differentiation mediated by the agrin-LRP4-MuSK signaling pathway.
Topics: Agrin; Cell Differentiation; LDL-Receptor Related Proteins; Neuromuscular Junction; Receptors, Cholinergic; Signal Transduction
PubMed: 23178848
DOI: 10.1007/s00018-012-1209-9 -
News in Physiological Sciences : An... Oct 2002The heparan sulfate proteoglycan agrin is responsible for the formation, maintenance, and regeneration of the neuromuscular junction. In the central nervous system,... (Review)
Review
The heparan sulfate proteoglycan agrin is responsible for the formation, maintenance, and regeneration of the neuromuscular junction. In the central nervous system, agrin is widely expressed and concentrated at interneuronal synapses, but its function during synaptogenesis remains controversial. Instead, evidence for additional functions of agrin during axonal growth, establishment of the blood-brain barrier, and Alzheimer's disease is accumulating.
Topics: Agrin; Alzheimer Disease; Animals; Central Nervous System; Humans; Synapses
PubMed: 12270958
DOI: 10.1152/nips.01390.2002 -
Arthritis Research & Therapy 2010Agrin plays a crucial role in the maintenance of the neuromuscular junction. However, it is expressed in other tissues as well, including T lymphocytes, where cell... (Review)
Review
Agrin plays a crucial role in the maintenance of the neuromuscular junction. However, it is expressed in other tissues as well, including T lymphocytes, where cell activation induces its expression. Agrin from activated T cells has the capacity to induce aggregation of key receptors and to regulate signalling. Interestingly, T cells isolated from patients with systemic lupus erythematosus over-express Agrin and its co-stimulation with the T cell receptor enhances production of pathogenic cytokines. These early studies point to an important function for Agrin in T cell biology and make the case for a more thorough and systematic investigation into its role in the immune system.
Topics: Agrin; Antigen-Presenting Cells; Humans; Immune System; Immunological Synapses; Lymphocyte Activation; Signal Transduction; T-Lymphocytes
PubMed: 20398335
DOI: 10.1186/ar2957 -
Annals of the New York Academy of... May 1998
Review
Topics: Agrin; Animals; Cytoskeletal Proteins; Dystroglycans; Dystrophin; Membrane Glycoproteins; Models, Neurological; Muscle, Skeletal; Muscular Dystrophies; Neuromuscular Junction; Receptors, Growth Factor
PubMed: 9668217
DOI: 10.1111/j.1749-6632.1998.tb10905.x -
Blood Sep 2011
Topics: Agrin; Animals; Cell Proliferation; Female; Hematopoiesis; Hematopoietic Stem Cells; Male; Stem Cell Niche
PubMed: 21903897
DOI: 10.1182/blood-2011-06-361253 -
Clinical Cancer Research : An Official... Mar 2022There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the...
PURPOSE
There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus-related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus-related neoplasia and to predict neoplastic progression.
EXPERIMENTAL DESIGN
Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus-related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus-related neoplasia from 321 patients in three independent cohorts.
RESULTS
Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus-related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus-related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus-related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%.
CONCLUSIONS
We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.
Topics: Agrin; Barrett Esophagus; Biomarkers; Esophageal Neoplasms; Humans; Tumor Suppressor Protein p53
PubMed: 34785582
DOI: 10.1158/1078-0432.CCR-21-2822 -
Current Topics in Membranes 2015Several members of the proteoglycan family are integral components of basement membranes; other proteoglycan family members interact with or bind to molecular residents... (Review)
Review
Several members of the proteoglycan family are integral components of basement membranes; other proteoglycan family members interact with or bind to molecular residents of the basement membrane. Proteoglycans are polyfunctional molecules, for they derive their inherent bioactivity from the amino acid motifs embedded in the core protein structure as well as the glycosaminoglycan (GAG) chains that are covalently attached to the core protein. The presence of the covalently attached GAG chains significantly expands the "partnering" potential of proteoglycans, permitting them to interact with a broad spectrum of targets, including growth factors, cytokines, chemokines, and morphogens. Thus proteoglycans in the basement membrane are poised to exert diverse effects on the cells intimately associated with basement membranes.
Topics: Agrin; Animals; Basement Membrane; Heparan Sulfate Proteoglycans; Humans
PubMed: 26610917
DOI: 10.1016/bs.ctm.2015.09.001