Agrin: A protein component of the synaptic basal lamina. It has been shown to induce clustering of acetylcholine receptors on the surface of muscle fibers and other synaptic molecules in both synapse regeneration and development.Receptors, Cholinergic: Cell surface proteins that bind acetylcholine with high affinity and trigger intracellular changes influencing the behavior of cells. Cholinergic receptors are divided into two major classes, muscarinic and nicotinic, based originally on their affinity for nicotine and muscarine. Each group is further subdivided based on pharmacology, location, mode of action, and/or molecular biology.Receptor Aggregation: Chemically stimulated aggregation of cell surface receptors, which potentiates the action of the effector cell.Dystroglycans: Dystrophin-associated proteins that play role in the formation of a transmembrane link between laminin-2 and DYSTROPHIN. Both the alpha and the beta subtypes of dystroglycan originate via POST-TRANSLATIONAL PROTEIN PROCESSING of a single precursor protein.Neuromuscular Junction: The synapse between a neuron and a muscle.Synaptic Membranes: Cell membranes associated with synapses. Both presynaptic and postsynaptic membranes are included along with their integral or tightly associated specializations for the release or reception of transmitters.Muscle Fibers, Skeletal: Large, multinucleate single cells, either cylindrical or prismatic in shape, that form the basic unit of SKELETAL MUSCLE. They consist of MYOFIBRILS enclosed within and attached to the SARCOLEMMA. They are derived from the fusion of skeletal myoblasts (MYOBLASTS, SKELETAL) into a syncytium, followed by differentiation.Carbocyanines: Compounds that contain three methine groups. They are frequently used as cationic dyes used for differential staining of biological materials.British Columbia: A province of Canada on the Pacific coast. Its capital is Victoria. The name given in 1858 derives from the Columbia River which was named by the American captain Robert Gray for his ship Columbia which in turn was named for Columbus. (From Webster's New Geographical Dictionary, 1988, p178 & Room, Brewer's Dictionary of Names, 1992, p81-2)New England: The geographic area of New England in general and when the specific state or states are not indicated. States usually included in this region are Maine, New Hampshire, Vermont, Massachusetts, Connecticut, and Rhode Island.Gift Giving: The bestowing of tangible or intangible benefits, voluntarily and usually without expectation of anything in return. However, gift giving may be motivated by feelings of ALTRUISM or gratitude, by a sense of obligation, or by the hope of receiving something in return.IndianaPhosphopyruvate Hydratase: A hydro-lyase that catalyzes the dehydration of 2-phosphoglycerate to form PHOSPHOENOLPYRUVATE. Several different isoforms of this enzyme exist, each with its own tissue specificity.Glutamate Decarboxylase: A pyridoxal-phosphate protein that catalyzes the alpha-decarboxylation of L-glutamic acid to form gamma-aminobutyric acid and carbon dioxide. The enzyme is found in bacteria and in invertebrate and vertebrate nervous systems. It is the rate-limiting enzyme in determining GAMMA-AMINOBUTYRIC ACID levels in normal nervous tissues. The brain enzyme also acts on L-cysteate, L-cysteine sulfinate, and L-aspartate. EC 4.1.1.15.Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate via direct electrical coupling with ELECTRICAL SYNAPSES. Several other non-synaptic chemical or electric signal transmitting processes occur via extracellular mediated interactions.Arthropods: Members of the phylum Arthropoda, composed of organisms having a hard, jointed exoskeleton and paired jointed legs. It includes the class INSECTS and the subclass ARACHNIDA, many species of which are important medically as parasites or as vectors of organisms capable of causing disease in man.Lead Radioisotopes: Unstable isotopes of lead that decay or disintegrate emitting radiation. Pb atoms with atomic weights 194-203, 205, and 209-214 are radioactive lead isotopes.Fossils: Remains, impressions, or traces of animals or plants of past geological times which have been preserved in the earth's crust.Muscles: Contractile tissue that produces movement in animals.Crustacea: A large subphylum of mostly marine ARTHROPODS containing over 42,000 species. They include familiar arthropods such as lobsters (NEPHROPIDAE), crabs (BRACHYURA), shrimp (PENAEIDAE), and barnacles (THORACICA).Motor Neurons: Neurons which activate MUSCLE CELLS.Muscle, Skeletal: A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles.Pectinidae: A large family of mollusks in the class BIVALVIA, known commonly as scallops. They possess flat, almost circular shells and are found in all seas from shallow water to great depths.Utrophin: An autosomally-encoded 376-kDa cytoskeletal protein that is similar in structure and function to DYSTROPHIN. It is a ubiquitously-expressed protein that plays a role in anchoring the CYTOSKELETON to the PLASMA MEMBRANE.SwitzerlandReceptors, Nicotinic: One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for NICOTINE over MUSCARINE. They are generally divided into muscle-type and neuronal-type (previously ganglionic) based on pharmacology, and subunit composition of the receptors.IllinoisAcetylcholine: A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system.Cartilage, Articular: A protective layer of firm, flexible cartilage over the articulating ends of bones. It provides a smooth surface for joint movement, protecting the ends of long bones from wear at points of contact.Cartilage: A non-vascular form of connective tissue composed of CHONDROCYTES embedded in a matrix that includes CHONDROITIN SULFATE and various types of FIBRILLAR COLLAGEN. There are three major types: HYALINE CARTILAGE; FIBROCARTILAGE; and ELASTIC CARTILAGE.Chondrocytes: Polymorphic cells that form cartilage.Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans.Low Density Lipoprotein Receptor-Related Protein-1: A LDL-receptor related protein involved in clearance of chylomicron remnants and of activated ALPHA-MACROGLOBULINS from plasma.LDL-Receptor Related Proteins: A family of proteins that share sequence similarity with the low density lipoprotein receptor (RECEPTORS, LDL).Acute Kidney Injury: Abrupt reduction in kidney function. Acute kidney injury encompasses the entire spectrum of the syndrome including acute kidney failure; ACUTE KIDNEY TUBULAR NECROSIS; and other less severe conditions.Renal Replacement Therapy: Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys.Sepsis: Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by HYPOTENSION despite adequate fluid infusion, it is called SEPTIC SHOCK.Shock, Septic: Sepsis associated with HYPOTENSION or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to LACTIC ACIDOSIS; OLIGURIA; or acute alteration in mental status.Kidney: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.Biological Markers: Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc.Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Muscular Atrophy, Spinal: A group of disorders marked by progressive degeneration of motor neurons in the spinal cord resulting in weakness and muscular atrophy, usually without evidence of injury to the corticospinal tracts. Diseases in this category include Werdnig-Hoffmann disease and later onset SPINAL MUSCULAR ATROPHIES OF CHILDHOOD, most of which are hereditary. (Adams et al., Principles of Neurology, 6th ed, p1089)Survival of Motor Neuron 1 Protein: A SMN complex protein that is essential for the function of the SMN protein complex. In humans the protein is encoded by a single gene found near the inversion telomere of a large inverted region of CHROMOSOME 5. Mutations in the gene coding for survival of motor neuron 1 protein may result in SPINAL MUSCULAR ATROPHIES OF CHILDHOOD.SMN Complex Proteins: A complex of proteins that assemble the SNRNP CORE PROTEINS into a core structure that surrounds a highly conserved RNA sequence found in SMALL NUCLEAR RNA. They are found localized in the GEMINI OF COILED BODIES and in the CYTOPLASM. The SMN complex is named after the Survival of Motor Neuron Complex Protein 1, which is a critical component of the complex.Survival of Motor Neuron 2 Protein: A SMN complex protein that is closely-related to SURVIVAL OF MOTOR NEURON 1 PROTEIN. In humans, the protein is encoded by an often duplicated gene found near the inversion centromere of a large inverted region of CHROMOSOME 5.Ribonucleoproteins, Small Nuclear: Highly conserved nuclear RNA-protein complexes that function in RNA processing in the nucleus, including pre-mRNA splicing and pre-mRNA 3'-end processing in the nucleoplasm, and pre-rRNA processing in the nucleolus (see RIBONUCLEOPROTEINS, SMALL NUCLEOLAR).Spinal Muscular Atrophies of Childhood: A group of recessively inherited diseases that feature progressive muscular atrophy and hypotonia. They are classified as type I (Werdnig-Hoffman disease), type II (intermediate form), and type III (Kugelberg-Welander disease). Type I is fatal in infancy, type II has a late infantile onset and is associated with survival into the second or third decade. Type III has its onset in childhood, and is slowly progressive. (J Med Genet 1996 Apr:33(4):281-3)Fucosyltransferases: Enzymes catalyzing the transfer of fucose from a nucleoside diphosphate fucose to an acceptor molecule which is frequently another carbohydrate, a glycoprotein, or a glycolipid molecule. Elevated activity of some fucosyltransferases in human serum may serve as an indicator of malignancy. The class includes EC 2.4.1.65; EC 2.4.1.68; EC 2.4.1.69; EC 2.4.1.89.FucoseGuanosine Diphosphate Fucose: A nucleoside diphosphate sugar formed from GDPmannose, which provides fucose for lipopolysaccharides of bacterial cell walls, and for blood group substances and other glycoproteins.Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction.

Globular domains of agrin are functional units that collaborate to induce acetylcholine receptor clustering. (1/304)

Agrin, an extracellular matrix protein involved in neuromuscular junction formation, directs clustering of postsynaptic molecules, including acetylcholine receptors (AChRs). This activity resides entirely in the C-terminal portion of the protein, which consists of three laminin-like globular domains (G-domains: G1, G2 and G3) and four EGF-like repeats. Additionally, alternate mRNA splicing yields G-domain variants G2(0,4) with 0- or 4-amino-acid inserts, and G3(0, 8,11,19) with 0-, 8-, 11- or 19-amino-acid inserts. In order to better understand the contributions of individual domains and alternate splicing to agrin activity, single G-domains and covalently linked pairs of G-domains were expressed as soluble proteins and their AChR clustering activity measured on cultured C2 myotubes. These analyses reveal the following: (1) While only G3(8) exhibits detectable activity by itself, all G-domains studied (G1, G2(0), G2(4), G3(0) and G3(8)) enhance G3(8) activity when physically linked to G3(8). This effect is most pronounced when G2(4) is linked to G3(8) and is independent of the order of the G-domains. (2) The deletion of EGF-like repeats enhances activity. (3) Increasing the physical separation between linked G1 and G3(8) domains produces a significant increase in activity; similar alterations to linked G2 and G3(8) domains are without effect. (4) Clusters induced by two concatenated G3(8) domains are significantly smaller than all other agrin forms studied. These data suggest that agrin G-domains are the functional units which interact independently of their specific organization to yield AChR clustering. G-domain synergism resulting in biological output could be due to physical interactions between G-domains or, alternatively, independent interactions of G-domains with cell surface receptors which require spatially localized coactivation for optimal signal transduction.  (+info)

Constitutively active MuSK is clustered in the absence of agrin and induces ectopic postsynaptic-like membranes in skeletal muscle fibers. (2/304)

In skeletal muscle fibers, neural agrin can direct the accumulation of acetylcholine receptors (AChR) and transcription of AChR subunit genes from the subsynaptic nuclei. Although the receptor tyrosine kinase MuSK is required for AChR clustering, it is less clear whether MuSK regulates gene transcription. To elucidate the role of MuSK in these processes, we constructed a constitutively active MuSK receptor, MuSKneuTMuSK, taking advantage of the spontaneous homodimerization of the transmembrane domain of neuT, an oncogenic variant of the neu/erbB2 receptor. In the extrasynaptic region of innervated muscle fibers, MuSKneuTMuSK formed highly concentrated aggregates that colocalized with AChR clusters. Associated with MuSK-induced AChR clusters was a normal complement of synaptic proteins. Moreover, transcription of the AChR-epsilon subunit gene was increased, albeit via an indirect mechanism by MuSK-induced aggregation of erbB receptors and neuregulin. Although neural agrin was not required, the activity of MuSKneuTMuSK was nevertheless potentiated by ectopic expression of a muscle agrin isoform inactive in AChR clustering. To define the role of the kinase domain in the formation of a postsynaptic-like membrane, a second fusion receptor, neuneuTMuSK, which included the MuSK kinase but not the MuSK extracellular domain, was expressed. Significantly, neuneuTMuSK induced AChR clusters that colocalized with aggregates of endogenous MuSK. Taken together, it was concluded that the MuSK kinase domain is sufficient to initiate the recruitment of additional MuSK receptors, which then develop into highly concentrated aggregates by means of a positive feedback loop to induce a postsynaptic membrane in the absence of neural agrin.  (+info)

Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. (3/304)

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with beta-amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to beta-amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.  (+info)

Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction. (4/304)

Agrin induces synaptic differentiation at the skeletal neuromuscular junction (NMJ); both pre- and postsynaptic differentiation are drastically impaired in its absence. Multiple alternatively spliced forms of agrin that differ in binding characteristics and bioactivity are synthesized by nerve and muscle cells. We used surgical chimeras, isoform-specific mutant mice, and nerve-muscle cocultures to determine the origins and nature of the agrin required for synaptogenesis. We show that agrin containing Z exons (Z+) is a critical nerve-derived inducer of postsynaptic differentiation, whereas neural isoforms containing a heparin binding site (Y+) and all muscle-derived isoforms are dispensable for major steps in synaptogenesis. Our results also suggest that the requirement of agrin for presynaptic differentiation is mediated indirectly by its ability to promote postsynaptic production or localization of appropriate retrograde signals.  (+info)

Roles of rapsyn and agrin in interaction of postsynaptic proteins with acetylcholine receptors. (5/304)

At the neuromuscular junction, aggregates of acetylcholine receptors (AChRs) are anchored in the muscle membrane by association with rapsyn and other postsynaptic proteins. We have investigated the interactions between the AChR and these proteins in cultured C2 myotubes before and after treatment with agrin, a nerve-derived protein that induces AChRs to cluster. When AChRs were isolated from detergent extracts of untreated C2 myotubes, they were associated with rapsyn and, to a lesser degree, with utrophin, beta-dystroglycan, MuSK, and src-related kinases, but not with syntrophin. Treatment with agrin increased the association of AChRs with MuSK, a receptor tyrosine kinase that forms part of the agrin receptor complex, without affecting other interactions. Analysis of rapsyn-deficient myotubes, which do not form protein clusters in response to agrin, revealed that rapsyn is required for association of the AChR with utrophin and beta-dystroglycan, and for the agrin-induced increase in association with MuSK, but not for constitutive interactions with MuSK and src-related kinases. In rapsyn -/- myotubes, agrin caused normal tyrosine phosphorylation of AChR-associated and total MuSK, whereas phosphorylation of the AChR beta subunit, both constitutive and agrin-induced, was strongly reduced. These results show first that aneural myotubes contain preassembled AChR protein complexes that may function in the assembly of the postsynaptic apparatus, and second that rapsyn, in addition to its role in AChR phosphorylation, mediates selected protein interactions with the AChR and serves as a link between the AChR and the dystrophin/utrophin glycoprotein complex.  (+info)

Evidence of an agrin receptor in cortical neurons. (6/304)

Agrin plays a key role in directing the differentiation of the vertebrate neuromuscular junction. Understanding agrin function at the neuromuscular junction has come via molecular genetic analyses of agrin as well as identification of its receptor and associated signal transduction pathways. Agrin is also expressed by many populations of neurons in brain, but its role remains unknown. Here we show, in cultured cortical neurons, that agrin induces expression of the immediate early gene c-fos in a concentration-dependent and saturable manner, as expected for a signal transduction pathway activated by a cell surface receptor. Agrin is active in cortical neurons at picomolar concentrations, is Ca(2+) dependent, and is inhibited by heparin and staurosporine. Despite marked differences in acetylcholine receptor (AChR)-clustering activity, all alternatively spliced forms of agrin are equally potent inducers of c-fos in cortical neurons. A similar, isoform-independent response to agrin was also observed in cultures prepared from the hippocampus and cerebellum. Only agrin with high AChR-clustering activity was effective in cultured muscle, whereas non-neuronal cells were agrin insensitive. Although consistent with a receptor tyrosine kinase model similar to the muscle-specific kinase-myotube-associated specificity component complex in muscle, our data suggest that CNS neurons express a unique agrin receptor. Evidence that neuronal signal transduction is mediated via an increase in intracellular Ca(2+) means that agrin is well situated to influence important Ca(2+)-dependent functions in brain, including neuronal growth, differentiation, and adaptive changes in gene expression associated with synaptic remodeling.  (+info)

Distinct domains of MuSK mediate its abilities to induce and to associate with postsynaptic specializations. (7/304)

Agrin released from motor nerve terminals activates a muscle-specific receptor tyrosine kinase (MuSK) in muscle cells to trigger formation of the skeletal neuromuscular junction. A key step in synaptogenesis is the aggregation of acetylcholine receptors (AChRs) in the postsynaptic membrane, a process that requires the AChR-associated protein, rapsyn. Here, we mapped domains on MuSK necessary for its interactions with agrin and rapsyn. Myotubes from MuSK(-/)- mutant mice form no AChR clusters in response to agrin, but agrin-responsiveness is restored by the introduction of rat MuSK or a Torpedo orthologue. Thus, MuSK(-/)- myotubes provide an assay system for the structure-function analysis of MuSK. Using this system, we found that sequences in or near the first of four extracellular immunoglobulin-like domains in MuSK are required for agrin responsiveness, whereas sequences in or near the fourth immunoglobulin-like domain are required for interaction with rapsyn. Analysis of the cytoplasmic domain revealed that a recognition site for the phosphotyrosine binding domain-containing proteins is essential for MuSK activity, whereas consensus binding sites for the PSD-95/Dlg/ZO-1-like domain-containing proteins and phosphatidylinositol-3-kinase are dispensable. Together, our results indicate that the ectodomain of MuSK mediates both agrin- dependent activation of a complex signal transduction pathway and agrin-independent association of the kinase with other postsynaptic components. These interactions allow MuSK not only to induce a multimolecular AChR-containing complex, but also to localize that complex to a primary scaffold in the postsynaptic membrane.  (+info)

Formation of the neuromuscular junction. Agrin and its unusual receptors. (8/304)

Synapses are essential relay stations for the transmission of information between neurones and other cells. An ordered and tightly regulated formation of these structures is crucial for the functioning of the nervous system. The induction of the intensively studied synapse between nerve and muscle is initiated by the binding of neurone-specific isoforms of the basal membrane protein agrin to receptors on the surface of myotubes. Agrin activates a receptor complex that includes the muscle-specific kinase and most likely additional, yet to be identified, components. Receptor activation leads to the aggregation of acetylcholine receptors (AChR) and other proteins of the postsynaptic apparatus. This activation process has unique features which distinguish it from other receptor tyrosine kinases. In particular, the autophosphorylation of the kinase domain, which usually induces the recruitment of adaptor and signalling molecules, is not sufficient for AChR aggregation. Apparently, interactions of the extracellular domain with unknown components are also required for this process. Agrin binds to a second protein complex on the muscle surface known as the dystrophin-associated glycoprotein complex. This binding forms one end of a molecular link between the extracellular matrix and the cytoskeleton. While many components of the machinery triggering postsynaptic differentiation have now been identified, our picture of the molecular pathway causing the redistribution of synaptic proteins is still incomplete.  (+info)

Agrin is an extracellular matrix protein that directs neuromuscular junction formation. Early signal transduction events in agrin-mediated postsynaptic differentiation include activation of a receptor tyrosine kinase and phosphorylation of acetylcholine receptors (AChRs), but later steps in this pathway are unknown. Here, we have investigated the role of intracellular calcium in agrin-induced AChR clustering on cultured myotubes. Clamping intracellular calcium levels by loading with the fast chelator BAPTA inhibited agrin-induced AChR aggregation. In addition, preexisting AChR aggregates dispersed under these conditions, indicating that the maintenance of AChR clusters is similarly dependent on intracellular calcium fluxes. The decrease in AChR clusters in BAPTA-loaded cells was dose-dependent and reversible, and no change in the number or mobility of AChRs was observed. Clamping intracellular calcium did not block agrin-induced tyrosine phosphorylation of the AChR beta-subunit, indicating that
Agrin, an extracellular matrix-associated protein extracted from synapse-rich tissues, induces the accumulation of acetylcholine receptors (AChRs) and other synaptic components into discrete patches on cultured myotubes. The appearance of agrin-like molecules at neuromuscular junctions suggests that it may direct synaptic organization in vivo. In the present study we examined the role of extracellular matrix components in agrin-induced differentiation. We used immunohistochemical techniques to visualize the spatial and temporal distribution of laminin, a heparan sulfate proteoglycan (HSPG), fibronectin, and type IV collagen on cultured chick myotubes during agrininduced aggregation of AChRs. Myotubes displayed significant amounts of laminin and HSPG, lesser amounts of type IV collagen, and little, if any, fibronectin. Agrin treatment caused cell surface laminin and HSPG to patch, while collagen and fibronectin distributions were generally unaffected. Many of the agrin-induced laminin and HSPG patches
TY - JOUR. T1 - O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. AU - Kim, Mi Lyang. AU - Chandrasekharan, Kumaran. AU - Glass, Matthew. AU - Shi, Shaolin. AU - Stahl, Mark C.. AU - Kaspar, Brian. AU - Stanley, Pamela. AU - Martin, Paul T.. PY - 2008/10/29. Y1 - 2008/10/29. N2 - Protein O-fucosyltransferase 1 (Pofut1) transfers fucose to serine or threonine on proteins, including Notch receptors, that contain EGF repeats with a particular consensus sequence. Here we demonstrate that agrin is O-fucosylated in a Pofut1-dependent manner, and that this glycosylation can regulate agrin function. Fucosylation of recombinant C45 agrin, both active (neural, z8) and inactive (muscle, z0) splice forms, was eliminated when agrin was overexpressed in Pofut1-deficient cells or by mutation of a consensus site for Pofut1 fucosylation (serine 1726 in the EGF4 domain). Loss of O-fucosylation caused a gain of function for muscle agrin such that it stimulated AChR ...
Signaling between nerve and muscle occurs at neuromuscular junctions (NMJs), which consist of specialized and precisely apposed pre- and postsynaptic structures separated by a synaptic cleft (Sanes and Lichtman 1999). Agrin, a heparan sulfate proteoglycan of ∼400-600 kD, is essential for the induction and organization of the postsynaptic structures (McMahan 1990; Gautam et al. 1996; Cohen et al. 1997; Jones et al. 1997; Meier et al. 1997; Rimer et al. 1997). Agrin is synthesized by motor neurons, transported to axon terminals, and released into the synaptic cleft of NMJs, where it binds to the basal lamina (Magill-Solc and McMahan 1988, Magill-Solc and McMahan 1990; Cohen and Godfrey 1992; Reist et al. 1992). Motor neurons express a mixture of agrin isoforms, alternatively spliced at two sites (A and B in chick, y and z in rat) in their COOH-terminal halves (Ruegg et al. 1992; Rupp et al. 1992; Hoch et al. 1993). The neural isoform of agrin containing inserts of four and eight amino acids at ...
At the neuromuscular junction, aggregates of acetylcholine receptors (AChRs) are anchored in the muscle membrane by association with rapsyn and other postsynaptic proteins. We have investigated the interactions between the AChR and these proteins in cultured C2 myotubes before and after treatment with agrin, a nerve-derived protein that induces AChRs to cluster. When AChRs were isolated from detergent extracts of untreated C2 myotubes, they were associated with rapsyn and, to a lesser degree, with utrophin, beta-dystroglycan, MuSK, and src-related kinases, but not with syntrophin. Treatment with agrin increased the association of AChRs with MuSK, a receptor tyrosine kinase that forms part of the agrin receptor complex, without affecting other interactions. Analysis of rapsyn-deficient myotubes, which do not form protein clusters in response to agrin, revealed that rapsyn is required for association of the AChR with utrophin and beta-dystroglycan, and for the agrin-induced increase in association ...
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. NOS inhibitors completely blocked agrin-induced AChR aggregation in cultured embryonic muscle cells. Application of NO donors to muscle cells induced AChR clustering in the absence of agrin. Our results indicate that NOS activity is necessary for postsynaptic differentiation of embryonic NMJs and that NOS is a likely participant in the agrin-MuSK signaling pathway of skeletal muscle cells ...
Objectives Osteoarthritis (OA) is a leading cause of disability for which there is no cure. The identification of molecules supporting cartilage homeostasis and regeneration is therefore a major pursuit in musculoskeletal medicine. Agrin is a heparan sulfate proteoglycan which, through binding to low-density lipoprotein receptor-related protein 4 (LRP4), is required for neuromuscular synapse formation. In other tissues, it connects the cytoskeleton to the basement membrane through binding to α-dystroglycan. Prompted by an unexpected expression pattern, we investigated the role and receptor usage of agrin in cartilage. Methods Agrin expression pattern was investigated in human osteoarthritic cartilage and following destabilisation of the medial meniscus in mice. Extracellular matrix (ECM) formation and chondrocyte differentiation was studied in gain and loss of function experiments in vitro in three-dimensional cultures and gain of function in vivo, using an ectopic cartilage formation assay in ...
BACKGROUND: One of the main causes of acute kidney injury (AKI) in patients treated on an intensive care unit (ICU) is sepsis. The identification of new biomarkers indicating the early development and future course of AKI are of utmost medical interest. The C-terminal agrin fragment (CAF) is measurable in blood serum and might reflect kidney function. Therefore, this study evaluates CAF in patients presenting to an internal ICU with severe sepsis or septic shock. Serum levels of CAF are correlated with biomarkers of kidney function, markers of systemic inflammation, and the presence of AKI and renal replacement therapy (RRT ...
During neuromuscular synapse formation, motor axons induce clustering of acetylcholine receptors (AChRs) in the muscle fiber membrane. The protein agrin, originally isolated from the basal lamina of the synaptic cleft, is synthesized and secreted by motoneurons and triggers formation of AChR cluster …
Prior studies on dystroglycan support dystroglycan as an agrin-binding protein. More specifically, data suggests that the carbohydrate residues on dystroglycan may be involved in binding to agrin. However, genetic and functional studies on dystroglycans role in agrin-mediated acetylcholine receptor (AChR) clustering remain unclear. Evidence points toward an indirect role for dystroglycan, a role which is important for the aggregation and stabilization of micro-clusters. The question of what regions of dystroglycan are functionally important for its role in agrin-induced AChR clustering is still unanswered. In an attempt to answer this question, we created beta-dystroglycan deletion and point mutants, and expressed these mutants in C2 muscle cells. Next, we assayed transfected myotubes for their responsiveness to agrin by measuring the number of AChR clusters per myotube segment. Last, we characterized a previously unknown protein-lipid interaction for dystroglycan. Our results demonstrate that ...
Glomerular charge selectivity has been attributed to anionic heparan sulfate proteoglycans (HSPGs) in the glomerular basement membrane (GBM). Agrin is the predominant GBM-HSPG, but evidence that it contributes to the charge barrier is lacking, because newborn agrin-deficient mice die from neuromuscular defects. To study agrin in adult kidney, a new conditional allele was used to generate podocyte-specific knockouts. Mutants were viable and displayed no renal histopathology up to 9 months of age. Perlecan, a HSPG normally confined to the mesangium in mature glomeruli, did not appear in the mutant GBM, which lacked heparan sulfate. Moreover, GBM agrin was found to be derived primarily from podocytes. Polyethyleneimine labeling of fetal kidneys revealed anionic sites along both laminae rarae of the GBM that became most prominent along the subepithelial aspect at maturity; labeling was greatly reduced along the subepithelial aspect in agrin-deficient and conditional knockout mice. Despite this
Neuromuscular junction (NMJ) assembly is characterized by the clustering and neuronal alignment of acetylcholine receptors (AChRs). In this study we have addressed post-synaptic contributions to assembly that may arise from the NMJ basement membrane with cultured myotubes. We show that the cell surface-binding LG domains of non-neural (muscle) agrin and perlecan promote AChR clustering in the presence of laminin-2. This type of AChR clustering occurs with a several hour lag, requires muscle-specific kinase (MuSK), and is accompanied by tyrosine phosphorylation of MuSK and betaAChR. It also requires conjugation of the agrin or perlecan to laminin together with laminin polymerization. Furthermore, AChR clustering can be mimicked with antibody binding to non-neural agrin, supporting a mechanism of ligand aggregation. Neural agrin, in addition to its unique ability to cluster AChRs through its B/z sequence insert, also exhibits laminin-dependent AChR clustering, the latter enhancing and stabilizing ...
About Steve Burden. Dr. Burdens laboratory has made significant contributions to our current understanding of the signaling pathways for forming and maintaining neuromuscular synapse. His experiments led to the discovery of the neural signal, Agrin, a secreted, extracellular matrix protein that is necessary to form and stabilize neuromuscular synapses. His laboratory went on to identify Lrp4 as the muscle receptor for Agrin and to discover MuSK, the kinase that associates with Lrp4 and transduces the Agrin signal to stimulate postsynaptic differentiation. Further, his laboratory showed that Lrp4 acts bi-directionally, as Lrp4 not only serves as a muscle receptor for Agrin but also signals in a retrograde manner to motor neurons to control presynaptic differentiation. These studies have led to a good understanding of the signaling events that control synapse formation and provide a basis for understanding how dysfunction of this pathway causes neuromuscular disease and insights into the design ...
Formation of the neuromuscular junction during embryonic period is only partially understood. It is a multistep process requiring coordinated interactions between nerve terminals and muscle. - During week 9, i.e. beginning of the fetal period, the first neuromuscular junctions appear on the newly created myotubes (muscle fibers formed from the fusion of myoblasts into multi-nucleated fibers). - The growing end of motor neuron axons secret a protein called agrin. - MuSK is a receptor tyrosine kinase on muscle cell. Once activated by a signal protein (agrin in this case), the kinase domain of MuSK transfers a phosphate group from ATP to selected tyrosine side chains on itself. This process is called autophosphorylation. - Upon activation by agrin, MuSK signals via proteins (CK 2, Dok-7 and rapsyn) to induce clustering of acetocholine receptors (AChR). - Formation of clusters of AChR occur and are concentrated in the central regions of the myofibers. - ACh released by branching nerve endings causes ...
Formation of the neuromuscular junction during embryonic period is only partially understood. It is a multistep process requiring coordinated interactions between nerve terminals and muscle. - During week 9, i.e. beginning of the fetal period, the first neuromuscular junctions appear on the newly created myotubes (muscle fibers formed from the fusion of myoblasts into multi-nucleated fibers). - The growing end of motor neuron axons secret a protein called agrin. - MuSK is a receptor tyrosine kinase on muscle cell. Once activated by a signal protein (agrin in this case), the kinase domain of MuSK transfers a phosphate group from ATP to selected tyrosine side chains on itself. This process is called autophosphorylation. - Upon activation by agrin, MuSK signals via proteins (CK 2, Dok-7 and rapsyn) to induce clustering of acetocholine receptors (AChR). - Formation of clusters of AChR occur and are concentrated in the central regions of the myofibers. - ACh released by branching nerve endings causes ...
Laminin colocalization with AChR aggregates is disrupted on dystroglycan- myotubes. Wild-type (R1) and dystroglycan- myotubes (3C12) were treated overnight with
Sigma-Aldrich offers abstracts and full-text articles by [Tohru Tezuka, Akane Inoue, Taisuke Hoshi, Scott D Weatherbee, Robert W Burgess, Ryo Ueta, Yuji Yamanashi].
β-Catenin and Acetylcholine Receptor Clustering. Bin Zhang, Shiwen Luo, Xian-Ping Dong, Xian Zhang, Chunming Liu, Zhenge Luo, Wen-Cheng Xiong, and Lin Mei. (see pages 3968-3973). Its a story that has touched the careers of many neuroscientists: the clustering of acetylcholine receptors (AChRs) at the neuromuscular junction. This week, Zhang et al. add β-catenin to a list of molecular characters that already includes agrin, rapysn, and MuSK (muscle-specific tyrosine kinase). The authors found β-catenin in a two-hybrid screen using rapsyn as bait. They confirmed that the interaction was direct, and that β-catenin coprecipitated with AChR complexes in control myotubes, but not in myotubes derived from rapsyn−/− mice. In a nicely controlled set of experiments, suppression of β-catenin by a short hairpin RNA reduced agrin-induced clustering of AChRs in C2C12 myoblasts. Although β-catenin is multifunctional, its action here did not involve the Wnt signaling pathway. Rather, an interaction ...
Martin Smith, professor of anatomy and neurobiology in the School of Medicine, and his UCI colleagues discovered that agrin -- a protein that directs synapse formation between nerve and muscle cells -- can also inhibit the function of "pumps" that control sodium and potassium levels within cells.. These pumps, called sodium-potassium ATPases -- or sodium pumps, for short -- are especially important in electrically excitable cells, where they provide the basis for electrical impulses, known as action potentials, which are responsible for muscle contraction and signaling between nerve cells in the brain. They do this by pumping sodium out of a cell and pumping potassium in, setting up an electrochemical gradient -- in a sense, turning the cell into a battery. If this activity isnt properly moderated, uncontrollable electrical impulses can be triggered, which is one of the cellular mechanisms behind an epileptic seizure, for instance.. This is where agrin comes into action. The UCI researchers ...
Glomerulonephritis is most commonly an autoimmune-induced inflammatory event wherein infiltration of the kidney by macrophages results in loss of renal function...
Glomerulonephritis is most commonly an autoimmune-induced inflammatory event wherein infiltration of the kidney by macrophages results in loss of renal function...
A genomic interrogation of homosexuality turns up speculative links between genetic elements and sexual orientation, but researchers say the study is too small to be significant. 6 Comments. ...
TY - JOUR. T1 - COOH-terminal collagen Q (COLQ) mutants causing human deficiency of endplate acetylcholinesterase impair the interaction of ColQ with proteins of the basal lamina. AU - Arredondo, Juan. AU - Lara, Marian. AU - Ng, Fiona. AU - Gochez, Danielle A.. AU - Lee, Diana C.. AU - Logia, Stephanie P.. AU - Nguyen, Joanna. AU - Maselli, Ricardo A. PY - 2014. Y1 - 2014. N2 - Collagen Q (ColQ) is a key multidomain functional protein of the neuromuscular junction (NMJ), crucial for anchoring acetylcholinesterase (AChE) to the basal lamina (BL) and accumulating AChE at the NMJ. The attachment of AChE to the BL is primarily accomplished by the binding of the ColQ collagen domain to the heparan sulfate proteoglycan perlecan and the COOH-terminus to the muscle-specific receptor tyrosine kinase (MuSK), which in turn plays a fundamental role in the development and maintenance of the NMJ. Yet, the precise mechanism by which ColQ anchors AChE at the NMJ remains unknown. We identified five novel ...
Botulinum toxin type-A (Btx-A), a powerful therapeutic tool in various medical specialties, requires repeated injections to maintain its effect. Therefore, novel methods to prolong the effective duration time of Btx-A are highly needed. Rats were assigned to three major groups: control group (n = 30), Btx-A group (n = 30), and IGF-1 Ab groups. IGF-1 Ab groups were composed by sub-groups A1-A5 (each has 25 rats) for the subsequent IGF-1Ab dose-effect study. Muscle strength was determined by a survey system for rat lower limbs nerve and muscle function. Muscle-specific receptor tyrosine kinase (MuSK), Insulin-like growth factor binding protein-5 (IGFBP5), and growth-associated protein, 43-kDa (GAP43) were determined by real-time polymerase chain reactions (PCRs) and Western blot. We found that Btx-A decreased the muscle strength, with a paralysis maintained for 70 days. IGF-1Ab prolonged the effective duration time of Btx-A. Real-time PCRs and Western blot showed that IGF-1Ab delayed the increase of
Many hormones and enzymes that were historically derived coq10 powder from animal sources are now synthesized by firefly luciferase enzyme recombinant protein expression, then harvested hirudin and refined from host cells.To purchase thrombin express recombinant proteins, carefully selected buy enzymes sequences of DNA must be introduced chrondroitin sulfate into a hosts genome. Taking portions of metallothionein the genetic code from one organism alpha-2-macroglobulin Protein and placing these into the cell abl protein nuclei of another is a form ACHE antibody of cloning. This is done via insertion beta actin protein of a sequence of recombinant DNA that Acvr2b encodes for the desired protein ADAMTS-4 into the nucleus, which initiates how to get adiponectin expression of the gene by transcribing ADRB1 it into RNA. Recombinant proteins are AFP protein assembled when pieces of mRNA RAGE protein carrying information from the DNA agrin protein migrate to the ribosomes from the Human ...
The first signs of synapse function The decision to form a synapse The sticky synapse Converting growth cones to presynaptic terminals Receptor clustering and postsynaptic differentiation at the NMJ Agrin is a transynaptic clustering signal at the NMJ Receptor clustering signals in the CNS Scaffold proteins and receptor aggregation in the CNS Innervation increases receptor expression and insertion Synaptic activity regulates receptor density Maturation of transmission and receptor isoform transitions Maturation of transmitter reuptake Short-term plasticity Appearance of synaptic inhibition Is inhibition really inhibitory during development?. Summary 9. Refinement of synaptic connections The early pattern of connections Functional synapses are eliminated Many axonal arborizations are eliminated or refined The Sensory Environment Influences Synaptic Connections Activity Influences Synapse Elimination at the NMJ Synapse refinement is reflected in sensory coding properties Activity contributes to ...
PMCID: PMC3863416. 2012. Buttermore ED, Piochon C. Wallace M, Philpot B, Hansel C, Bhat MA. 2012. Pinceau organization in the cerebellum requires distinct functions of Neurofascin in Purkinje and basket neurons during postnatal development. J Neurosci. 32(14), pp. 4724-4742.. Chen YC, Lin YQ, Banerjee S, Venken K, Li J, Ismat A, Chen K, Duraine L, Bellen HJ, Bhat MA. 2012. Drosophila Neuroligin 2 is required presynaptically and postsynaptically for proper synaptic differentiation and synaptic transmission. J. Neurosci. 32(45), pp. 16018-30.. Coutinho-Budd J, Ghukasyan V, Zylka MJ, and Polleux F. 2012. The F-BAR domains from srGAP1, srGAP2, and srGAP3 differentially regulate membrane deformation. J. Cell Sci. 125(14), pp. 3390-401.. Dumitru, R, Gama, V, Fagan, M, Bower, J, Pevny, L, and Deshmukh, M. 2012. Human embryonic stem cells have constitutively active bax at the golgi and are primed to undergo rapid apoptosis. Mol. Cell. 5, pp. 573-83. Higginbotham H, Eom TY, Mariani LE, Bachleda A, Hirt ...
... has always dreamed big, and tonight he showed off his biggest reverie yet: the fully electric Tesla Semi. Powered by a massive battery and capable of hauling 80,000 pounds, it can ramble 500 miles between charges. Itll even drive itself-on the highway, at least.1 And Musk promises production will start in 2019. The […]. Read More ». ...
Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice ...
A variable proportion of patients with generalized myasthenia gravis (MG) have autoantibodies to muscle mass specific tyrosine kinase (MuSK). MuSK expression and/or inhibit the conversation with LRP4. We prepared MuSK IgG, monovalent Fab fragments, IgG1-3 and IgG4 fractions from MuSK-MG plasmas. We asked whether the antibodies caused endocytosis of MuSK in MuSK-transfected cells or if they inhibited binding of LRP4 to MuSK in co-immunoprecipitation experiments. In parallel, we investigated their ability to reduce Ribitol AChR clusters in C2C12 myotubes induced by a) agrin, reflecting neuromuscular development, and b) by Dok7- overexpression, generating AChR clusters that more closely resemble the adult neuromuscular synapse. Total IgG, IgG4 Ribitol or IgG1-3 MuSK antibodies were not endocytosed unless cross-linked by divalent anti-human IgG. MuSK IgG, Fab fragments and IgG4 inhibited the binding of LRP4 to MuSK and reduced agrin-induced Ribitol AChR clustering in C2C12 cells. By contrast, IgG1-3 ...
Takahiro Fukazawa, Masaya Matsumoto, Takeshi Imura, Elham Khalesi, Teruyuki Kajiume, Yumi Kawahara, Keiji Tanimoto and Louis Yuge; Electrical stimulation accelerates neuromuscular junction formation through ADAM19/neuregulin/ErbB signaling in vitro; Neuroscience Letters Volume 545, 17 June 2013, Pages 29-34 (doi: 10.1016/j.neulet.2013.04.006 ...
Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by a breakdown in communication between nerves and muscles, resulting in weakness and rapid fatigue. The muscle weakness associated with myasthenia gravis increases when one is active, but then improves after periods of rest. The degree of muscle weakness varies greatly between individuals.. Myasthenia gravis causes the immune system to produce antibodies that either block or destroy muscles receptor sites for the neurotransmitter acetylcholine. With some receptors blocked, the muscles receive fewer signals and subsequently prevent muscles from contracting, resulting in weakness. Production of the antibodies that block acetylcholine is likely triggered by the thymus, which is found to be abnormally large in people with myasthenia gravis. Sometimes the antibodies, rather than block receptor sites, block the function of a protein called muscle-specific receptor tyrosine kinase, which is involved in creating the ...
Postischemic hypothermia protects against loss of agrin and SPARC from the vascular basement membrane in global cerebral ischemia
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In the current study, the authors show that two strains of AAV, AAV-1 and AAV-2, were effective in transferring the mini-agrin gene to cells in two mouse models. The AAV-1 vector was given by systemic delivery - a single infusion into the abdominal cavity - a method the authors only recently described and which they used for the first time in this study to transfer a therapeutic gene. The AAV-2 vector was delivered locally, given by intramuscular injection to different muscles of the leg. With both approaches, muscle cells were able to assimilate and copy the genetic instructions for making mini-agrin. Once produced, the mini-agrin protein functionally took the place of the laminin alpha-2 protein by binding to the key proteins on either end, thus restoring the cells outside scaffolding and reestablishing the missing link to key structures inside the cell ...
As the β loop motif is sufficient for clustering of chimeric proteins and mutation of β Y390 impairs clustering of intact AChR (Borges and Ferns, 2001), phosphorylation must regulate protein interactions involved in AChR localization. Somewhat unexpectedly, our findings demonstrate that the β loop motif forms a regulated binding site for rapsyn. First, we found that agrin increased rapsyn/AChR association in parallel with β subunit phosphorylation, and that rapsyn was preferentially associated with phosphorylated AChR. Second, rapsyn bound the β loop Y390 region (20 aa) in overlay blots, although binding was not phosphorylation-dependent in this assay. One possible explanation is that Y390 phosphorylation induces a conformational change (Phan-Chan-Du et al., 2003) that promotes rapsyn binding to adjacent residues and this is probably not apparent in overlay blots because most protein is denatured. Alternatively, another muscle protein might form a tertiary complex with rapsyn and the β ...
The synapsin family consists of three neuronal-specific phosphoproteins associated with dynamic reorganization of the neuronal cytoskeleton. Synapsin I and II are implicated in axonal and synaptic differentiation, formation and maintenance, whereas the function of synapsin III is not as well defined …
Since the muscle looked normal, they turned their attention to the motor neuron and got another surprise. Working with Gerald Fischbach, a visiting professor at Rockefeller, the group artificially stimulated the motor axon and found that it was fully able to transmit electrical impulses to secrete its neurotransmitter and cause the muscle to twitch, even though the mice remained completely paralyzed. A more refined picture began to emerge: While Z+ agrin restores the cluster of receptors at the junction, it doesnt restore the ability of the motor neurons to fire ...
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TY - JOUR. T1 - Comment on "Tequila, a neurotrypsin ortholog, regulates long-term memory formation in Drosophila".. AU - Sonderegger, Peter. AU - Patthy, Laszlo. PY - 2007/6/22. Y1 - 2007/6/22. N2 - Didelot et al. (Reports, 11 August 2006, p. 851) claimed that Drosophila Tequila (Teq) and human neurotrypsin are orthologs and concluded that deficient long-term memory after Teq inactivation indicates that neurotrypsin plays its essential role for human cognitive functions through a similar mechanism. Our analyses suggest that Teq and neurotrypsin are not orthologous, leading us to question their equivalent roles in higher brain function.. AB - Didelot et al. (Reports, 11 August 2006, p. 851) claimed that Drosophila Tequila (Teq) and human neurotrypsin are orthologs and concluded that deficient long-term memory after Teq inactivation indicates that neurotrypsin plays its essential role for human cognitive functions through a similar mechanism. Our analyses suggest that Teq and neurotrypsin are not ...
Renegade immune system. Since the 1970s, its been understood that most MG is due to the immune systems mistaken attack on multiprotein structures called acetylcholine receptors, docking sites on muscle fibers that receive a chemical called acetylcholine from nerve cells. Normally, the presence of acetylcholine causes a muscle fiber to contract, allowing muscle activity to occur.. In most cases of MG, the immune systems inappropriate target is these docking sites. An immune response, in the form of immune system proteins called antibodies, blocks or destroys the acetylcholine receptors, preventing them from receiving the "go" signal from acetylcholine.. In fact, MG is a classic autoimmune disease, a type of disorder in which the body produces an immune response against itself.. These days, its known that the acetylcholine receptors are the most common but not the only target of the immune system in MG. In some people with MG, the target is a protein known as muscle-specific kinase, or MuSK. ...
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This paper focuses on exquisite musk secretion, uses of musk, production of musk, trade of musk, and taxonomy, distribution and conservation of musk deer.
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... muscle, skeletal, receptor tyrosine kinase Identifiers Symbol MUSK Entrez 4593 HUGO 7525 OMIM 601296 RefSeq NM_005592 UniProt O15146 Other data
Elon Musk, the man heading up SpaceX and Tesla, could be launching a new project with the aim of producing an implantable computer-brain interface device. This will be under a new company called Neuralink Corp.
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In this essay Someone called Soter examines the Drake Equation which asks how many technically advanced civilizations exist in our galaxy.. He also looks at the Fermi Paradox which questions why, if there are other technological civilizations nearby, we havent heard from them.. If civilizations exist in our galaxy with level of technology at least equal to our own, we might be able to detect some of them using radio telescopes.. And if civilizations exist with technologies far in advance of our own we might expect them to have colonized millions of habitable worlds in the Milky Way, and even to have visited our own planet.. Yet there is no evidence in the astronomical geological archaeological, or historical records that extraterrestrial civilizations exist or that visitors from other worlds have ever been to Earth.. Does that means as some have concluded that ours is the only civilizations in the galaxy ?. or could there be a natural self regulations mechanism that limits the intensive ...
Acetylcholine receptor (AChR) clusters of cultured rat myotubes, isolated by extraction with saponin (Bloch, R. J., 1984, J. Cell Biol. 99:984-993), contain a polypeptide that co-electrophoreses with purified muscle actins. A monoclonal antibody against actin reacts in immunoblots with this polypeptide and with purified actins. In indirect immunofluorescence, the antibody stains isolated AChR clusters only at AChR domains, strips of membrane within clusters that are rich in receptor. It also stains the postsynaptic region of the neuromuscular junction of adult rat skeletal muscle. Semiquantitative immunofluorescence analyses show that labeling by antiactin of isolated analyses show that labeling by antiactin of isolated AChR clusters is specific and saturable and that it varies linearly with the amount of AChR in the cluster. Filaments of purified gizzard myosin also bind preferentially at AChR-rich regions, and this binding is inhibited by MgATP. These experiments suggest that actin is ...
AGRIN; ATRN; ATRNL1; CELSR1; CELSR2; CELSR3; CRELD1; HSPG2; LAMA1; LAMA2; LAMA3; LAMA4; LAMA5; LAMB1; LAMB2; LAMB3; LAMB4; ... AGRIN; CELSR1; CELSR2; CELSR3; CNTNAP1; CNTNAP2; CNTNAP3; CNTNAP3B; CNTNAP4; CNTNAP5; COL11A1; COL11A2; COL12A1; COL14A1; ...
Below is a list of human proteins containing the EGF-like domain: AGC1; AGRIN; AREG; ATRN; ATRNL1; BCAN; BMP1; BTC; C1S; CASPR4 ...
Moberg, Paul J.; Agrin, Rachel; Gur, Raquel E.; Gur, Ruben C.; Turetsky, Bruce I.; Doty, Richard L. (September 1999). " ...
May 1996). "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513-23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787. ... In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Upon activation by its ligand ... Furthermore, the nerve-derived organizing factor agrin fails to stimulate MuSK activation in muscle cells genetically null for ... agrin, MuSK signals via the proteins called Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Cell ...
Agrin, a heparin proteoglycan, and MuSK kinase are thought to help stabilize the accumulation of AChR in the central regions of ... In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Further, mice deficient in Dok- ... Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of ... "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513-23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787. Witzemann V ( ...
May 1996). "Agrin acts via a MuSK receptor complex". Cell. 85 (4): 513-23. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787. ...
For example, agrin was first isolated from Torpedo. Scribonius Largus, a first century physician, advised the use of a live ...
Also, ennui is very important for agrin function. Ennui is very important in nerve-dependent acetylcholine clustering and the ...
Agrin induces clustering of AchRs on the muscle surface and synapse formation is disrupted in agrin knockout mice. Agrin ... Agrin appears not to be a central mediator of CNS synapse formation and there is active interest in identifying signals that ... They also showed that the synaptogenic signal is produced by the nerve, and they identified the factor as Agrin. ...
It is activated by a nerve-derived proteoglycan called agrin. Upon activation by its ligand agrin, MuSK signals via the ...
The dystroglycan complex is also known to serve as an agrin receptor in muscle, where it may regulate agrin-induced ... Gesemann M, Brancaccio A, Schumacher B, Ruegg MA (Jan 1998). "Agrin is a high-affinity binding protein of dystroglycan in non- ... Actin-binding protein Agrin GRCh38: Ensembl release 89: ENSG00000173402 - Ensembl, May 2017 GRCm38: Ensembl release 89: ... is a functional agrin receptor". Cell. 77 (5): 675-86. doi:10.1016/0092-8674(94)90052-3. PMID 8205617. Ibraghimov-Beskrovnaya O ...
Burkin DJ, Kim JE, Gu M, Kaufman SJ (2000). "Laminin and alpha7beta1 integrin regulate agrin-induced clustering of ...
Other less frequent antibodies are found against LRP4, Agrin and titin proteins. Human leukocyte antigens have been associated ...
Agrin, a protein linked to heparan sulfate basement membrane nephrin Renal corpuscle. GBM is #1. Jarad, G.; Miner, J. H. (2009 ...
The rapsyn protein interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without ... This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK protein), AChRs and the AChR-clustering protein rapsyn, ... Han H, Noakes PG, Phillips WD (Sep 1999). "Overexpression of rapsyn inhibits agrin-induced acetylcholine receptor clustering in ... "Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein ...
The agrin gene codes for a family of basal lamina proteins that differ in function and distribution. Neuron 8, 691-699. PMID ... An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature 413, 302-307. PMID ... Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice. EMBO Mol Med 3, 465-479. PMID ...
Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Rüegg MA (August 2011). "Apoptosis inhibitors and mini-agrin have additive ... Given that the technology for mini-agrin administration to skeletal muscle in human subjects is not yet available, omigapil is ... Omigapil coupled with mini-agrin overexpression works as a dual treatment that enhances mechanical load bearing ability and ... "Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice". EMBO Molecular Medicine. 3 ( ...
Agrin binds to a muscle-specific kinase (MuSK) receptor in the post-synaptic membrane, and this in turn leads to downstream ... The axon of the motoneuron releases agrin, a proteoglycan that initiates a cascade that eventually leads to AChR association. ... In motor neurons, Wnt-3 works with Agrin to promote growth cone enlargement, axon branching and synaptic vesicle clustering. ... AChR experiences multimerization within the post-synaptic membrane largely due to the signaling molecule Agrin. ...
Nate Agrin and Ken-ichi Ueda continued work on the site with Sean McGregor, a web developer. In 2011, Ueda began collaboration ... iNaturalist.org began in 2008 as a UC Berkeley School of Information Master's final project of Nate Agrin, Jessica Kline, and ...
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The protein agrin, which concentrates acetylcholine receptors during human embryonic development, was first isolated from this ...
Rapsyn interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, ... This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK), acetylcholine receptors (AChRs) and the AChR-clustering ...
The encoded proteins are structurally similar to laminin, slit, and agrin, other proteins involved in axon guidance and ...
The C-terminal domain contains multiple extracellular SEA (sea urchin sperm protein, enterokinase, and agrin) modules, a ... enterokinase and agrin) module in cleavage of membrane-tethered mucins". The FEBS Journal. 272 (11): 2901-11. doi:10.1111/j. ...
Lupa, MT; Caldwell, JH (Nov 1991). "Effect of Agrin on the Distribution of Acetylcholine Receptors and Sodium Channels on Adult ...
The requirement for Agrin and MuSK in the formation of the NMJ was demonstrated primarily by knockout mouse studies. In mice ... Agrin was first identified by the U.J. McMahan laboratory, Stanford University. During development, the growing end of motor ... The nerve secretes agrin, resulting in phosphorylation of the MuSK receptor. It seems that the MuSK receptor recruits casein ... Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during ...
We suggest that binding of these TGFβ family members to agrin may have a dual function: agrin may serve as a reservoir for ... Based on analysis of the evolutionary history of agrin we suggest that agrins growth factor binding function is more ancient ... in the case of TGFβ1 Agrin N-term caused a slight increase in activity in reporter assays. Our finding that agrin binds members ... we have explored the interaction of the N-terminal part of rat agrin (Agrin-Nterm) with members of the TGFβ family using ...
However, blocking agrin function with agrin-specific antibodies, or reducing agrin expression with antisense oligonucleotides ... 1996) Neural agrin activates a high-affinity receptor in C2 muscle cells that is unresponsive to muscle agrin. J Neurosci 16: ... Purified recombinant agrin isoforms (50 pm) (Campanelli et al., 1996) were added as described for the oligonucleotides. Agrin ( ... Agrin mRNA and immunoreactivity can be detected in CNS neurons, where the temporal pattern of expression of agrin parallels ...
Here we report that treating chick myotubes with agrin caused an increase in phosphorylation of … ... Agrin causes acetylcholine receptors (AChRs) on chick myotubes in culture to aggregate, forming specializations that resemble ... and was blocked by treatments known to block agrin-induced AChR aggregation. Anti-phosphotyrosine antibodies labeled agrin- ... Agrin induces phosphorylation of the nicotinic acetylcholine receptor Neuron. 1991 Jun;6(6):869-78. doi: 10.1016/0896-6273(91) ...
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She currently practices at Rachel N Agrin-Silva MD and is affiliated with Beth Israel D... ... Rachel Agrin-Silva, MD is a practicing Pediatrician in Norwood, MA. ... Agrin-Silvas Background Bio Rachel Agrin-Silva, MD is a practicing Pediatrician in Norwood, MA. She currently practices at ... Agrin-Silva accepts multiple insurance plans including Aetna, Harvard Pilgrim and Tufts Health Plan. Dr. Agrin-Silva is board ...
The putative agrin receptor binds ligand in a calcium-dependent manner and aggregates during agrin-induced acetylcholine ... Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation [1].. *Agrin protein binds the amyloidogenic peptide ... Colocalization with agrin binding sites at synapses supports the hypothesis that the alpha3NKA is a neuronal agrin receptor [6] ... An agrin fragment that acts as a competitive antagonist depresses action potential frequency, showing that endogenous agrin ...
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Agrins AChR clustering activity is regulated by alternative mRNA splicing. Agrin splice forms having inserts at two sites (y ... Agrin binding to the cell surface showed analogous properties: heparin inhibits the binding of only those agrin isoforms ... Here, the binding of four recombinant agrin isoforms to heparin, to alpha-dystroglycan (a component of an agrin receptor), and ... The results show that alternative splicing of agrin regulates its binding to heparin and suggest that agrins interaction with ...
Background of Agrin antibody. Kit Component:. - KN212203G1, AGRN gRNA vector 1 in pCas-Guide vector. - KN212203G2, AGRN gRNA ... Western blot analysis of Agrin expression in HEK293T (A); NIH3T3 (B); PC12 (C) whole cell lysates.. *CPA3098-100ul ...
Motor neuron-derived agrin activates MuSK via binding to MuSKs coreceptor Lrp4, and genetic defects in agrin underlie a ... The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses.. [Tohru Tezuka, ... Here, we show that forced expression of Dok-7 in muscle enhanced MuSK activation in mice lacking agrin or Lrp4 and restored ... Thus, it was hypothesized that MuSK needs agrin together with Lrp4 and Dok-7 to achieve sufficient activation to surmount ...
The protein agrin, originally isolated from the basal lamina of the synaptic cleft, is synthesized and secreted by motoneurons ... Defective neuromuscular synaptogenesis in agrin-deficient mutant mice Cell. 1996 May 17;85(4):525-35. doi: 10.1016/s0092-8674( ... The protein agrin, originally isolated from the basal lamina of the synaptic cleft, is synthesized and secreted by motoneurons ... We show here postsynaptic AChR aggregates are markedly reduced in number, size, and density in muscles of agrin-deficient ...
We also describe anti-agrin staining in nonjunctional regions of muscle. We conclude the following: (a) agrin-like molecules ... Agrin-like molecules at synaptic sites in normal, denervated, and damaged skeletal muscles.. N E Reist, C Magill, U J McMahan ... We found that anti-agrin antibodies intensely stained the synaptic cleft of frog and chicken as well as that of rays, that ... Several lines of evidence have led to the hypothesis that agrin, a protein extracted from the electric organ of Torpedo, is ...
We showed that Agrin functions in cellular migration, invasion and tumor growth. However, the exact mechanisms by which Agrins ... Our evidences reveal that Agrin binds to its co-receptor(s) Lrp4 and subsequently activates MuSK to mediate oncogenic effects ... Abstract 5036: Elucidating an oncogenic role of an extracellular matrix protein, Agrin, in hepatocellular carcinoma. Sayan ... More importantly, Lrp4-MuSK as well as integrin-FAK pathways are crucial downstream signaling axes of Agrins functions in ...
Binding of Injected Agrin to the Surface of Muscle Fibers. Neural Agrin.. Neural agrin bound uniformly along the entire length ... Muscle Agrin.. Muscle agrin bound to the surface of innervated and denervated muscle fibers essentially as neural agrin with ... Muscle agrin, however, did not cause aggregation of AChRs. As was the case for neural agrin, nonradioactive muscle agrin ... an excess of nonradioactive muscle agrin did not decrease subsequent binding of neural agrin nor did an excess of neural agrin ...
Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in ... Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in ... Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in ...
... interact with each other and with a signalling molecule called agrin to influence the development of the neuromuscular junction ... and agrin. (D) Control (lanes 1-3), agrin Z0 (lanes 4-6), agrin Z8 (lanes 7-9), or agrin Z19 (lanes 10-12) containing culture ... C2C12 cells express muscle agrin, which binds to APP as shown in Figure 9. APPs effect could be studied in agrin-/- or KD ... Because APP could bind both muscle and neuronal agrin, an interesting question is if APP acts by aggregating agrin. The ...
Treatment with agrin increased the association of AChRs with MuSK, a receptor tyrosine kinase that forms part of the agrin ... Treatment with agrin increased the association of AChRs with MuSK, a receptor tyrosine kinase that forms part of the agrin ... Fuhrer, C; Gautam, M; Sugiyama, J E; Hall, Z W (1999). Roles of rapsyn and agrin in interaction of postsynaptic proteins with ... In rapsyn -/- myotubes, agrin caused normal tyrosine phosphorylation of AChR-associated and total MuSK, whereas phosphorylation ...
We found that agrin is most abundant in lung, kidney, and brain. Only a little agrin was detected in skeletal muscle, and no ... We found that agrin is most abundant in lung, kidney, and brain. Only a little agrin was detected in skeletal muscle, and no ... Agrin is a high-affinity binding protein of dystroglycan in non-muscle tissue ZORA Maintenance. Maintenance: Thursday, 22 March ... Gesemann, M; Brancaccio, A; Schumacher, B; Ruegg, M A (1998). Agrin is a high-affinity binding protein of dystroglycan in non- ...
The N-terminal half of agrin was necessary for induction of filopodia, and over-expression of TM-agrin in a neuronal cell line ... Here we demonstrate that agrin positively regulates neuronal filopodia. Over-expression of TM-agrin caused the formation of ... Conversely, suppression of agrin expression by siRNA reduced the number of filopodia. Time lapse analysis indicated that ... By positively regulating filopodia in developing neurons, TM-agrin may influence the pattern of neurite outgrowth and synapse ...
The question of what regions of dystroglycan are functionally important for its role in agrin-induced AChR clustering is still ... Next, we assayed transfected myotubes for their responsiveness to agrin by measuring the number of AChR clusters per myotube ... More specifically, data suggests that the carbohydrate residues on dystroglycan may be involved in binding to agrin. However, ... Structural and Functional Aspects of Dystroglycan During Agrin -Mediated Acetylcholine Receptor Clustering at the Mammalian ...
C-terminal fragment of agrin (CAF), a proteoglycan of the glomerular and tubular basement membrane, have been recently ... Agrin serves also as a ubiquitous component of the extracellular matrix [10]. Cleavage of agrin by the serine protease ... Neurotrypsin cleaves agrin locally at the synapse. FASEB J. 2008;22(6):1861-73.View ArticlePubMedGoogle Scholar. ... AKI acute kidney injury, AUC area under the curve, CAF C-terminal agrin fragment, CI confidence interval, Cyst-C cystatin-C, IL ...
mRNA expression of agrin, AChR-ε and AChR-γ. The mRNA expression of agrin, AChR-ε and AChR-γ in each experimental group is ... Furthermore, although AChR aggregation by agrin is recognised, the upstream regulation of agrin remains poorly understood. ... this process is regulated by agrin.4 During denervation, agrin expression is downregulated and AChR-γ replaces AChR-ε ... Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain 2014;137(Pt 9):2429-43 ...
Agrin activates YAP in human skin fibroblast (HSF) through integrin mediated adhesion and Lrp4/MuSK receptor-mediated signaling ... Effects of agrin silencing on MuSK expression and phosphorylation. Effects of agrin on YAP may also depend on Lrp4/MuSK ... Effects of agrin on the regulation of YAP activation can also be achieved through the interactions between agrin and Lrp4/MuSK ... Effects of agrin silencing on FAK expression and phosphorylation. Effects of agrin on YAP depend on integrin mediated adhesion ...
Results Agrin was detected in normal cartilage but was progressively lost in OA. In vitro, agrin knockdown resulted in reduced ... Prompted by an unexpected expression pattern, we investigated the role and receptor usage of agrin in cartilage. Methods Agrin ... Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in ... 2015) Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro ...
  • Heparan sulfate glycosaminoglycans covalently linked to the agrin protein have been shown to play a role in the clustering of AChR. (wikipedia.org)
  • Here we report that treating chick myotubes with agrin caused an increase in phosphorylation of the AChR beta, gamma, and delta subunits. (nih.gov)
  • H-7, a potent inhibitor of several protein serine kinases, blocked agrin-induced phosphorylation of the gamma and delta subunits, but did not prevent either agrin-induced AChR aggregation or phosphorylation of the beta subunit. (nih.gov)
  • Experiments with anti-phosphotyrosine antibodies demonstrated that agrin caused an increase in tyrosine phosphorylation of the beta subunit that began within 30 min of adding agrin to the myotube cultures, reached a plateau by 3 hr, and was blocked by treatments known to block agrin-induced AChR aggregation. (nih.gov)
  • These results suggest that agrin-induced tyrosine phosphorylation of the beta subunit may play a role in regulating AChR distribution. (nih.gov)
  • The protein agrin, originally isolated from the basal lamina of the synaptic cleft, is synthesized and secreted by motoneurons and triggers formation of AChR clusters on cultured myotubes. (nih.gov)
  • We show here postsynaptic AChR aggregates are markedly reduced in number, size, and density in muscles of agrin-deficient mutant mice. (nih.gov)
  • Neural agrin causes a dose-dependent appearance of AChR aggregates, which persist ≥7 wk after a single application. (rupress.org)
  • Muscle agrin does not cluster AChRs and at 10 times the concentration of neural agrin does not reduce binding or AChR-aggregating activity of neural agrin. (rupress.org)
  • Electrical muscle activity affects the stability of agrin binding and the number, size, and spatial distribution of the neural agrin-induced AChR aggregates. (rupress.org)
  • Expression of neural agrin in transfected cells followed by its release and deposition on neighboring fibers induced multiple AChR aggregates. (rupress.org)
  • In cultured myotubes, APP synergistically increases agrin-induced acetylcholine receptor (AChR) clustering. (elifesciences.org)
  • We have investigated the interactions between the AChR and these proteins in cultured C2 myotubes before and after treatment with agrin, a nerve-derived protein that induces AChRs to cluster. (uzh.ch)
  • Analysis of rapsyn-deficient myotubes, which do not form protein clusters in response to agrin, revealed that rapsyn is required for association of the AChR with utrophin and beta-dystroglycan, and for the agrin-induced increase in association with MuSK, but not for constitutive interactions with MuSK and src-related kinases. (uzh.ch)
  • In rapsyn -/- myotubes, agrin caused normal tyrosine phosphorylation of AChR-associated and total MuSK, whereas phosphorylation of the AChR beta subunit, both constitutive and agrin-induced, was strongly reduced. (uzh.ch)
  • However, genetic and functional studies on dystroglycan's role in agrin-mediated acetylcholine receptor (AChR) clustering remain unclear. (illinois.edu)
  • The question of what regions of dystroglycan are functionally important for its role in agrin-induced AChR clustering is still unanswered. (illinois.edu)
  • Next, we assayed transfected myotubes for their responsiveness to agrin by measuring the number of AChR clusters per myotube segment. (illinois.edu)
  • Objective To investigate the effects of electroacupuncture (EA) on mRNA and protein expression of agrin, acetylcholine receptor (AChR)-ε and AChR-γ in a rat model of tibialis anterior muscle atrophy induced by sciatic nerve injection injury, and to examine the underlying mechanism of action. (bmj.com)
  • The sciatic nerve functional index (SFI), tibialis anterior muscle weight, muscle fibre cross-sectional area (CSA), and changes in agrin, AChR-ε, and AChR-γ expression levels were analysed. (bmj.com)
  • mRNA/protein expression of agrin and AChR-ε were downregulated and AChR-γ expression was detectable (vs zero expression in the CON/CON+EA groups). (bmj.com)
  • Conclusions EA may alleviate tibialis anterior muscle atrophy induced by sciatic nerve injection injury by upregulating agrin and AChR-ε and downregulating AChR-γ. (bmj.com)
  • Underlying these changes are decreases in the molar amounts of transcripts encoding the neuron-specific isoforms agrin8 and agrin19, homologous to rat agrin proteins that have high AChR aggregating activity. (escholarship.org)
  • Here, we have investigated the role of intracellular calcium in agrin-induced AChR clustering on cultured myotubes. (umassmed.edu)
  • Clamping intracellular calcium levels by loading with the fast chelator BAPTA inhibited agrin-induced AChR aggregation. (umassmed.edu)
  • Clamping intracellular calcium did not block agrin-induced tyrosine phosphorylation of the AChR beta-subunit, indicating that intracellular calcium fluxes are likely to act downstream from or parallel to AChR phosphorylation. (umassmed.edu)
  • Finally, the targets of the intracellular calcium are likely to be close to the calcium source, since agrin-induced AChR clustering was unaffected in cells loaded with EGTA, a slower-binding calcium chelator. (umassmed.edu)
  • Loss of O-fucosylation caused a gain of function for muscle agrin such that it stimulated AChR clustering and MuSK phosphorylation in cultured myotubes at levels normally only found with the neural splice form. (elsevier.com)
  • These data are consistent with a role for Pofut1 in AChR aggregation during synaptogenesis via the regulation of the synaptogenic activity of muscle agrin. (elsevier.com)
  • The inclusion of these amino acids is specific for neuronally expressed isoforms of this protein, and these amino acids are necessary for MuSK activation and the AChR clustering activity of agrin. (alpfmedical.info)
  • Thus, while agrin is made by both nerves and muscles, only nerves made isoforms of the protein that were active in AChR clustering, refining but not disproving the agrin hypothesis. (alpfmedical.info)
  • At the same time, AChR interaction with rapsyn and dystrobrevin and AChR phosphorylation decreased after agrin withdrawal from mutant myotubes. (jneurosci.org)
  • The overall cytoskeletal link of AChRs was weak but still strengthened by agrin in mutant cells, consistent with the normal formation but decreased stability of AChR clusters. (jneurosci.org)
  • We propose that VVA lectin increases the frequency of AChR clustering through a mechanism that is distinct from agrin signaling, and that may involve α-dystroglycan. (elsevier.com)
  • C2C12 skeletal muscle cell cultures were maintained, myoblasts were fused into myotubes, and then cultures were exposed to motor neuron derived agrin to enhance acetylcholine receptor (AChR) clustering. (biomedcentral.com)
  • The results reported here demonstrate that 1 μg/mL sodium nitrate was sufficient to decrease the frequency of agrin-induced AChR clustering without affecting myotube formation. (biomedcentral.com)
  • In addition, concentrations of sodium nitrate of 1 μg/mL or 100 μg/mL decreased gene expression of the myogenic transcription factor myogenin and AChR in correlation with the agrin-induced AChR clustering data. (biomedcentral.com)
  • These results reveal that sodium nitrate decreases the frequency of agrin-induced AChR clustering by a mechanism that includes myogenin and AChR gene expression. (biomedcentral.com)
  • Many of the agrin-induced laminin and HSPG patches colocalized with AChR patches, raising the possibility of a causal relationship between matrix patching and AChR accumulations. (semanticscholar.org)
  • However, patching of AChRs (complete within a few hours) preceded that of laminm or HSPG (not complete until 15-20 h), making it unlikely that matrix accumulations initiate AChR patching at agrin-induced sites. (semanticscholar.org)
  • Conversely, when AChR patching was blocked by treatment with anti-AChR antibody mAb 35, agrin was still able to effect patching of laminin and HSPG. (semanticscholar.org)
  • Taken together, these findings suggest that agrin-induced accumulations of AChR and laminin/HSPG are not mechanistically linked. (semanticscholar.org)
  • Several observations suggest that agrin-induced AChR patching occurs through a specific, physiological cellular mechanism. (semanticscholar.org)
  • Agrin effects myotubes in a dose-dependent manner, although at higher agrin levels the number of AChR patches per myotube plateaus off (Godfrey et al. (semanticscholar.org)
  • Our objective was to use the C2C12 cell culture model to test the hypothesis that both MyoD and myogenin were required for agrin-induced acetylcholine receptor (AChR) clustering and the fusion of myoblasts into myotubes. (scirp.org)
  • Fluorescence microscopy images were captured and then analyzed to assess agrin-induced AChR clustering with or without antibody treatment. (scirp.org)
  • We report that antibody to either MyoD or myogenin decreases the frequency of agrin-induced AChR clustering without affecting myotube formation. (scirp.org)
  • We conclude that agrin-induced AChR clustering requires both MyoD and myogenin. (scirp.org)
  • We show that the cell surface-binding LG domains of non-neural (muscle) agrin and perlecan promote AChR clustering in the presence of laminin-2. (unibas.ch)
  • Furthermore, AChR clustering can be mimicked with antibody binding to non-neural agrin, supporting a mechanism of ligand aggregation. (unibas.ch)
  • Neural agrin, in addition to its unique ability to cluster AChRs through its B/z sequence insert, also exhibits laminin-dependent AChR clustering, the latter enhancing and stabilizing its activity. (unibas.ch)
  • These findings provide evidence for cooperative and partially redundant MuSK-dependent functions of basement membrane in AChR assembly that can enhance neural agrin activity yet operate in its absence. (unibas.ch)
  • Such interactions may contribute to the assembly of aneural AChR clusters that precede neural agrin release as well as affect later NMJ development. (unibas.ch)
  • For example, the muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (Lrp4) and adaptor protein rapsyn are required for the formation of the spatially restricted pattern of the postsynaptic apparatus, including acetylcholine receptor (AChR) clusters, known as the endplate band, whereas motor nerve-derived signals such as agrin and acetylcholine (ACh) play opposing roles in the refinement and maintenance of the postsynaptic apparatus [ 3 - 13 ]. (plos.org)
  • We have applied purified recombinant chick neural and muscle agrin to rat soleus muscle in vivo and obtained the following results. (rupress.org)
  • Both neural and muscle agrin bind uniformly to the surface of innervated and denervated muscle fibers along their entire length. (rupress.org)
  • NT-1654 is a C-terminal fragment of mouse neural agrin. (readbyqxmd.com)
  • Fucosylation of recombinant C45 agrin, both active (neural, z8) and inactive (muscle, z0) splice forms, was eliminated when agrin was overexpressed in Pofut1-deficient cells or by mutation of a consensus site for Pofut1 fucosylation (serine 1726 in the EGF4 domain). (elsevier.com)
  • These defects primarily impair the function of neural y+z+ agrin and combine to cause a severe CMS phenotype, whereas y-z- agrin function in other tissues appears preserved. (elsevier.com)
  • Therefore, we performed a SILAC based quantitative proteomics of cell surface proteins in HCC lines and identified proteoglycan Agrin to be overexpressed and secreted in HCC. (aacrjournals.org)
  • Injected agrin is recovered from the muscles together with laminin and both proteins coimmunoprecipitate, indicating that agrin binds to laminin in vivo. (rupress.org)
  • Roles of rapsyn and agrin in interaction of postsynaptic proteins with acetylcholine receptors. (uzh.ch)
  • But after agrin withdrawal, clusters of these proteins disappeared rapidly in parallel with AChRs, revealing that SFKs are of general importance in postsynaptic stability. (jneurosci.org)
  • In turn, the researchers found that they could block these electrical impulses by introducing small fragments of agrin, which prevented the full agrin proteins from binding their sites on the sodium pump molecules and initiating action potentials. (innovations-report.com)
  • Agrin proteins are also expressed in heart tissue, and Smith notes that sodium pump inhibitors, such as digoxin, are commonly used to treat congestive heart failure. (innovations-report.com)
  • Incorporated into this basement membrane are also found proteins released by the nerve, such as agrin and neuregulin, which participate in the formation and maintenance of the NMJ. (scorcher.ru)
  • In comparison to unoperated age-matched controls, in situ hybridization with a pan-specific agrin cRNA probe demonstrated a significant decrease in neuronal agrin mRNA expression as a result of axotomy. (escholarship.org)
  • Agrin, a multidomain proteoglycan and neurotrypsin, a neuronal serine protease, are important for forming (neuromuscular) synapses. (readbyqxmd.com)
  • Motor neuronal repletion of the NMJ organizer, Agrin , modulates the severity of the spinal muscular atrophy disease phenotype in model mice. (neurotune.com)
  • We recently discovered that proteolytic cleavage of agrin by the neuronal serine protease neurotrypsin results in NMJ degeneration and, in turn, loss of muscle fibers, resulting in a sarcopenia-like muscle atrophy. (fsrmm.ch)
  • An isoform of agrin that does not induce postsynaptic specializations binds with high affinity to dystroglycan, a component of the dystrophin-glycoprotein complex. (uzh.ch)
  • Distinct localization of T cell Agrin during antigen presentation--evidence for the expression of Agrin receptor(s) in antigen-presenting cells. (semanticscholar.org)
  • Expression of agrin in HSF was downregulated by siRNA transfection. (alliedacademies.org)
  • In this study, expression of Agrin in Human Skin Fibroblast (HSF) was downregulated by siRNA transfection. (alliedacademies.org)
  • The expression of agrin in the liver has recently been described under physiologic and pathologic conditions. (elsevier.com)
  • We aimed to study the mRNA and protein expression of agrin in cholangiocarcinoma (CC) and focused on the differences between CC and hepatocellular carcinoma (HCC). (elsevier.com)
  • CC samples showed an even higher expression of agrin. (elsevier.com)
  • We also provide evidence for the expression of Agrin receptors in peripheral blood monocytes, dendritic cells and a fraction of B cells. (unesp.br)
  • These data show that the agrin isoform expressed in non-muscle tissue is a high-affinity binding partner of dystroglycan and they suggest that this interaction, like that between laminin and dystroglycan, may be important for the mechanical integrity of the tissue. (uzh.ch)
  • In the C-terminal half of the protein are four EGF-like repeats and three laminin-type globular G-domains (G). Agrin is alternatively spliced in its C-terminal half. (alpfmedical.info)
  • Agrin treatment caused cell surface laminin and HSPG to patch, while collagen and fibronectin distributions were generally unaffected. (semanticscholar.org)
  • It also requires conjugation of the agrin or perlecan to laminin together with laminin polymerization. (unibas.ch)
  • Stimulation of monocytes with recombinant Agrin induced the clustering of surface receptors, including major histocompatibility complex class II, activation of intracellular signalling cascades, as well as enhanced dsRNA-induced expression of pro-inflammatory cytokines interleukin-6 and tumour necrosis factor-a. (unesp.br)
  • Collectively, these results confirm the location of Agrin at the immunological synapse between T cells and antigen-presenting cells and justify further characterization of its receptors in the immune system. (unesp.br)
  • A possible explanation for such early abnormalities was impairment of neurotrypsin/Agrin system. (heighpubs.org)
  • The constitution of NMJ is physiologically boosted by the neurotrypsin/Agrin system. (heighpubs.org)
  • Excessive neurotrypsin activation and agrin cleavage-a pathogenic condition leading to sarcopenia-like muscle atrophy? (fsrmm.ch)
  • Thus, overexpression of the agrin-cleaving protease neurotrypsin in motoneurons installed the full sarcopenia phenotype in young-adult mice. (fsrmm.ch)
  • However, our studies of neurotrypsin-deficient mice and of mice co-expressing cleavage-resistant agrin together with overexpressed neurotrypsin indicated that age-dependent sarcopenia develops in the absence of neurotrypsin and is not prevented by cleavage-resistant agrin. (fsrmm.ch)
  • Agrin is cleaved by its specific protease neurotrypsin at two distinct sites, whereas cleavage at the beta site generates a 22 kDa C-terminal fragment (CAF22). (clinicaltrials.gov)
  • Recently, mice that either express extremely low levels of agrin transcripts or do not express highly active (z+) isoforms have been produced. (jneurosci.org)
  • Agrin splice forms having inserts at two sites (y and z) in the C-terminal region are highly active, but isoforms lacking these inserts are weakly active. (pnas.org)
  • Here, the binding of four recombinant agrin isoforms to heparin, to alpha-dystroglycan (a component of an agrin receptor), and to myoblasts was tested. (pnas.org)
  • Agrin binding to the cell surface showed analogous properties: heparin inhibits the binding of only those agrin isoforms containing this four-amino acid insert. (pnas.org)
  • Only a little agrin was detected in skeletal muscle, and no agrin was found in liver. (uzh.ch)
  • In a solid-phase radioligand binding assay, agrin bound to dystroglycan from lung, kidney, and skeletal muscle with a dissociation constant between 1.8 and 2.2 nM, while the affinity to brain-derived dystroglycan was 4.6 nM. (uzh.ch)
  • Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice. (nih.gov)
  • Methods Agrin expression pattern was investigated in human osteoarthritic cartilage and following destabilisation of the medial meniscus in mice. (surrey.ac.uk)
  • The SMA mice is treated with therapeutic Agrin biological NT-1654, from birth onwards. (heighpubs.org)
  • So far, the effects of agrin on muscle fibers have been studied in culture systems, transgenic animals, and in animals injected with agrin-cDNA constructs. (rupress.org)
  • Thus, the present approach provides a novel, simple, and efficient method for studying the effects of agrin on muscle under controlled conditions in vivo. (rupress.org)
  • To investigate the effects of agrin on YAP expression in Human Skin Fibroblast (HSF), and the possible mechanism. (alliedacademies.org)
  • Effects of agrin silencing on HSF proliferation, migration and invasion were investigated. (alliedacademies.org)
  • Similar, but less dramatic changes in agrin expression following axotomy were also observed in unoperated neurons on the contralateral side. (escholarship.org)
  • Major changes in agrin gene expression following axotomy but not denervation are consistant with the notion that agrin synthesized by ganglionic neurons exerts its effects in the periphery rather than at synapses formed between ciliary ganglion neurons and their preganglionic input. (escholarship.org)
  • We found that agrin is most abundant in lung, kidney, and brain. (uzh.ch)
  • Here we demonstrate that agrin is O-fucosylated in a Pofut1-dependent manner, and that this glycosylation can regulate agrin function. (elsevier.com)
  • In vitro, agrin knockdown resulted in reduced glycosaminoglycan content, downregulation of the cartilage transcription factor SOX9 and other cartilage-specific ECM molecules. (surrey.ac.uk)
  • The effects of antisense oligonucleotides were found to be highly specific because they were reversed by adding recombinant agrin and could not be detected in cultures from agrin-deficient animals. (jneurosci.org)