Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

O'Toole, John J.; Deyst, Katherine A.; Bowe, Mark A.; Nastuk, Mary A.; McKechnie, Beth A.; Fallon, Justin R.

doi:10.1073/pnas.93.14.7369

Cited by 73 publications

(69 citation statements)

References 40 publications

(61 reference statements)

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“…Because C -Ag 4,0 and C -Ag 0,0 lack AChR-clustering activity, their concentration in C OS-7 cell -conditioned media was determined using a two-site sandwich ELISA (Gesemann et al, 1995;O'Toole et al, 1996) using an anti-agrin monoclonal antibody Agr 530 [StressGen Hoch et al, 1994)] and a rabbit antiserum raised against a synthetic peptide corresponding to amino acids 1862-1893 of the mouse agrin sequence (Rupp et al, 1992). These antibodies recognize distinct epitopes common to all agrin isoforms.…”

Section: Methodsmentioning

confidence: 99%

Evidence of an Agrin Receptor in Cortical Neurons

1999

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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 2ϩ 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-myotubeassociated 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 2ϩ means that agrin is well situated to influence important Ca 2ϩ -dependent functions in brain, including neuronal growth, differentiation, and adaptive changes in gene expression associated with synaptic remodeling.

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Section: Methodsmentioning

confidence: 99%

Evidence of an Agrin Receptor in Cortical Neurons

1999

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“…These include dystroglycan, glycoconjugates, integrins, HB-GAM/pleitrophin, heparan sulfate proteoglycans, N-CAM, and laminins (Bowe et al 1994;Campanelli et al 1994Campanelli et al , 1996Gee et al 1994;Sugiyama et al 1994;, 1997Mook-Jung & Gordon 1995;Storms et al 1996;Daggett et al 1996;Gesemann et al 1996;O'Toole et al 1996;Hopf & Hoch 1996;Denzer et al 1997). Several of these have been implicated in AChR clustering based on studies in culture myotubes, but none has been shown to be critical for postsynaptic differentiation in vivo (reviewed in .…”

Section: Agrin Signalingmentioning

confidence: 99%

Development of the Vertebrate Neuromuscular Junction

Sanes

Lichtman

1999

Annu. Rev. Neurosci.

1,397

1,210

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We dedicate this review to the memory of our friend, colleague, and collaborator, John Paul Merlie , honoring his many contributions to the understanding of synaptic development. ABSTRACTWe describe the formation, maturation, elimination, maintenance, and regeneration of vertebrate neuromuscular junctions (NMJs), the best studied of all synapses. The NMJ forms in a series of steps that involve the exchange of signals among its three cellular components-nerve terminal, muscle fiber, and Schwann cell. Although essentially any motor axon can form NMJs with any muscle fiber, an additional set of cues biases synapse formation in favor of appropriate partners. The NMJ is functional at birth but undergoes numerous alterations postnatally. One step in maturation is the elimination of excess inputs, a competitive process in which the muscle is an intermediary. Once elimination is complete, the NMJ is maintained stably in a dynamic equilibrium that can be perturbed to initiate remodeling. NMJs regenerate following damage to nerve or muscle, but this process differs in fundamental ways from embryonic synaptogenesis. Finally, we consider the extent to which the NMJ is a suitable model for development of neuron-neuron synapses.

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“…When small peptides are inserted in these regions, the overall properties of agrin are modified significantly. Insertion of a four-amino-acid sequence at the y site confers heparin-binding properties (47). When the insertion is present, the binding of agrin to α-dystroglycan is inhibited by heparin.…”

Section: Expression and Functional Propertiesmentioning

confidence: 99%

“…By analogy to laminin and perlecan, this domain may self-assemble. Alternatively spliced variants of domain IV with insertion of small peptide sequences, 4-19 amino acid residues long, have been described (47). These short peptides can significantly influence the binding of agrin to heparin, α-dystroglycan, and the cell surface (46).…”

Section: General Structural Featuresmentioning

confidence: 99%

MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

Iozzo

1998

Annu. Rev. Biochem.

1,481

1,111

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The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant.The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined. CONTENTS

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Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface.

Cited by 73 publications

References 40 publications

Evidence of an Agrin Receptor in Cortical Neurons

Evidence of an Agrin Receptor in Cortical Neurons

Development of the Vertebrate Neuromuscular Junction

MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

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