Disease relevance of AGRN

• Alternative splicing of both the 8- and the 11-amino-acid exons results in expression of four distinct agrin transcripts in the ganglion [1].
• The agrin-deficient myotubes could also respond to neuron-induced AChR aggregation after coculturing with neuroblastoma cells [2].

High impact information on AGRN

• To test this hypothesis, we cocultured chick ciliary ganglion neurons with agrin-expressing CHO cells [3].
• One synaptic basal lamina protein, agrin, which influences postsynaptic muscle differentiation, has been suggested to influence nerve terminals as well [3].
• Ciliary ganglion neurons, but not sensory neurons, adhered five times as well to agrin-expressing cells as to untransfected cells [3].
• Finally, the synaptic vesicle protein synaptotagmin became concentrated at contacts between ciliary ganglion neurites and agrin-expressing cells [3].
• Our results demonstrate that transcripts encoding agrin proteins with high AChR aggregating activity are expressed exclusively by neurons in the ciliary ganglion and that alternative splicing of agrin mRNA is regulated during development and in a cell-specific manner [4].

Chemical compound and disease context of AGRN

• The early appearance of agrin mRNA coincides with the period during which acetylcholine receptors are being organized on ciliary ganglion neurons, consistent with the possibility that agrin contributes to neuron-neuron synapse formation in this pathway [5].

Biological context of AGRN

• Developmental expression and alternative splicing of chick agrin RNA [1].
• Measurement of agrin mRNA levels by competitive PCR showed that agrin gene expression in the ganglion increased dramatically between E8 and E10, was sustained at high levels from E10 to E14, and declined thereafter [1].
• We have examined agrin gene expression in the chick ciliary ganglion during normal embryonic development using in situ hybridization and quantitative PCR techniques [1].
• We have isolated a cDNA from a chick brain library that, based on sequence homology and expression experiments, codes for active agrin [6].
• Agrin induces phosphorylation of the nicotinic acetylcholine receptor [7].

Anatomical context of AGRN

• Agrin is a synaptic basal lamina protein that has been proposed to mediate motor neuron-induced clustering of acetylcholine receptors during development of the neuro-muscular junction [1].
• These results demonstrate that agrin is expressed in autonomic motor neurons of the peripheral nervous system and support a wider role for agrin as a synaptogenic protein, not limited to spinal motor neurons [1].
• Ganglia were specifically labeled by antisense agrin cRNA probes and the density of labeling changed during development [1].
• We isolated two cDNAs that encode isoforms of agrin, the basal lamina protein that mediates the motor neuron-induced aggregation of acetylcholine receptors on muscle fibers at the neuromuscular junction [8].
• Agrin is thought to mediate the motor neuron-induced aggregation of AChRs and AChE on the surface of muscle fibers at neuromuscular junctions [6].

Associations of AGRN with chemical compounds

• Due to the presence of cyclic GMP-dependent protein kinase (PKG) at the neuromuscular junction, we tested the ability of a PKG inhibitor to alter the agrin signaling cascade [9].
• Agrin's neurite inhibitory activity is confined to the N-terminal segment of the protein (agrin N150), which contains heparan sulfate (HS) and chondroitin sulfate (CS) side chains [10].
• These results suggest that agrin-induced tyrosine phosphorylation of the beta subunit may play a role in regulating AChR distribution [7].
• 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 [7].
• Agrin is a large, multidomain heparan sulfate proteoglycan that is associated with basement membranes of several tissues [11].

Regulatory relationships of AGRN

• However, a time course of agrin-induced clustering that focused on filamin revealed that most of the early AChR clusters (3-6 h) were not associated with detectable amounts of cytoskeletal material [12].

Other interactions of AGRN

• Even a muscle form of agrin that lacks intrinsic clustering activities by itself, significantly enhances neuregulin-induced clustering and insertion of AChRs [13].
• Agrin is a proteoglycan that can inhibit neurite outgrowth from multiple neuronal types when present as a substrate [10].
• Thus, our studies demonstrate that chick agrin is a HSPG that is prominent in the embryonic chick brain [14].
• Laminin, nidogen, agrin, collagen IV, and XVIII are major constituents of the retinal basal lamina [15].

Analytical, diagnostic and therapeutic context of AGRN

• Here, electron microscopy was used to determine the structure of agrin and to localize its binding site in laminin-1 [11].
• The cellular origin of the agrin-like molecules at synapses was examined in cross-species cocultures in which the neurons and muscle cells were obtained from embryos of Xenopus laevis and Rana pipiens [16].
• Immunocytochemistry demonstrated that agrin is expressed in developing brain, and is especially abundant in developing axonal tracts, in a distribution identical to the staining of the brain HSPG with monoclonal antibodies [14].
• Reverse transcription-polymerase chain reaction (RT-PCR) of E9 chick brain mRNA confirmed the existence of this agrin isoform in brain, although the novel splice variant represents a minor fraction of agrin mRNA in brain [17].
• The amino acid sequence of agrin encodes a protein with a molecular size of 220 kDa, whereas SDS-PAGE shows a diffuse band around 400 kDa [18].

References