Substrate-bound agrin induces expression of acetylcholine receptor epsilon-subunit gene in cultured mammalian muscle cells.

Jones, Graham; Herczeg, A.; Rüegg, Markus A.; Lichtsteiner, M.; Kröger, Stephan; Brenner, Hans Rudolf

doi:10.1073/pnas.93.12.5985

Cited by 80 publications

(83 citation statements)

References 35 publications

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“…These increases are in fact of similar magnitude to those reported recently by Jones et al (45) who examined the impact of both muscle and neural isoforms of agrin on expression of transcripts encoding the AChR ⑀-subunit. However, a major difference between the two studies is that we were able to observe an effect on utrophin gene expression without the necessity of agrin being substrate-bound (45). Although the reason for this difference remains currently obscure, it appears reasonable to assume that it likely arises from differences in culture conditions.…”

Section: Discussioncontrasting

confidence: 41%

“…In particular, recent experiments have revealed that Matrigel TM is capable of binding agrin (46,47). Since, in our experiments, myotube cultures are plated on Matrigel-coated plates, it appears likely that Torpedo agrin as well as recombinant agrin fragments may become bound to this substrate via an unknown mechanism (see Denzer et al (46,47) for further discussion) and therefore do not remain in a "soluble" form (45). Nonetheless, since the pattern of expression of the utrophin gene along muscle fibers resembles that of the ⑀-subunit gene (26,36,48), these results are coherent with the notion that expression of genes encoding membrane and cytoskeletal proteins of the postsynaptic membrane are co-regulated and therefore involve a common signal transduction pathway.…”

Section: Discussionmentioning

confidence: 98%

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Muscle and Neural Isoforms of Agrin Increase Utrophin Expression in Cultured Myotubes via a Transcriptional Regulatory Mechanism

Gramolini¹,

Burton²,

Tinsley³

et al. 1998

Journal of Biological Chemistry

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Duchenne muscular dystrophy is a prevalent X-linked neuromuscular disease for which there is currently no cure. Recently, it was demonstrated in a transgenic mouse model that utrophin could functionally compensate for the lack of dystrophin and alleviate the muscle pathology (Tinsley, J. M., Potter, A. C., Phelps, S. R., Fisher, R., Trickett, J. I., and Davies, K. E. (1996) Nature 384, 349 -353). In this context, it thus becomes essential to determine the cellular and molecular mechanisms presiding over utrophin expression in attempts to overexpress the endogenous gene product throughout skeletal muscle fibers. In a recent study, we showed that the nerve exerts a profound influence on utrophin gene expression and postulated that nerve-derived trophic factors mediate the local transcriptional activation of the utrophin gene within nuclei located in the postsynaptic sarcoplasm (Gramolini, A. O., Dennis, C. L., Tinsley, J. M., Robertson, G. S., Davies, K. E, Cartaud, J., and Jasmin, B. J. (1997) J. Biol. Chem. 272, 8117-8120). In the present study, we have therefore focused on the effect of agrin on utrophin expression in cultured C2 myotubes. In response to Torpedo-, muscle-, or nerve-derived agrin, we observed a significant 2-fold increase in utrophin mRNAs. By contrast, CGRP treatment failed to affect expression of utrophin transcripts. Western blotting experiments also revealed that the increase in utrophin mRNAs was accompanied by an increase in the levels of utrophin. To determine whether these changes were caused by parallel increases in the transcriptional activity of the utrophin gene, we transfected muscle cells with a 1.3-kilobase pair utrophin promoter-reporter (nlsLacZ) gene construct and treated them with agrin for 24 -48 h. Under these conditions, both muscle-and nerve-derived agrin increased the activity of ␤-galactosidase, indicating that agrin treatment led, directly or indirectly, to the transcriptional activation of the utrophin gene. Furthermore, this increase in transcriptional activity in response to agrin resulted from a greater number of myonuclei expressing the 1.3-kilobase pair utrophin promoter-nlsLacZ construct. Deletion of 800 base pairs 5 from this fragment decreased the basal levels of nlsLacZ expression and abolished the sensitivity of the utrophin promoter to exogenously applied agrin. In addition, site-directed mutagenesis of an N-box motif contained within this 800-base pair fragment demonstrated its essential contribution in this regulatory mechanism. Finally, direct gene transfer studies performed in vivo further revealed the importance of this DNA element for the synapse-specific expression of the utrophin gene along multinucleated muscle fibers. These data show that both muscle and neural isoforms of agrin can regulate expression of the utrophin gene and further indicate that agrin is not only involved in the mechanisms leading to the formation of clusters containing presynthesized synaptic molecules but that it can also participate in the local regulation of genes encoding s...

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Section: Discussioncontrasting

confidence: 41%

Section: Discussionmentioning

confidence: 98%

Muscle and Neural Isoforms of Agrin Increase Utrophin Expression in Cultured Myotubes via a Transcriptional Regulatory Mechanism

Gramolini¹,

Burton²,

Tinsley³

et al. 1998

Journal of Biological Chemistry

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“…The dependence of Na ϩ channel aggregation on agrin immobilization also may explain apparently conflicting re- sults by Corfas and Fischbach (1993) that Na ϩ channels in cultured chick myotubes are induced by ARIA / heregulin, but not by soluble agrin. As proposed here and previously (Jones et al, 1996(Jones et al, , 1997 for agrin-induced AChR gene expression, agrin attached to BL may stimulate the muscle fiber to secrete neuregulin and /or modif y the BL in such a way as to provide binding sites for muscle-derived N RG. Such N RG aggregates would, in turn, induce the ectopic Na ϩ channel aggregates.…”

Section: Accumulation Of Na ؉ Channels and The Formation Of Ectopic Jmentioning

confidence: 98%

“…By inducing ectopic secretion of neural agrin from muscle fibers in vitro and in vivo, we have shown recently that neural agrin, immobilized presumably by attachment to the extracellular matrix, is sufficient to induce ectopic adult-type AChR aggregates (Jones et al, 1996(Jones et al, , 1997. Given the functional similarities of ectopic agrin-induced AChR clusters to AChRs at normal mature endplate membrane, we now show that the neural agrin isoform cAgrin 7A4B8 also induces the localized expression of structural components characteristic of a normal postsynaptic apparatus.…”

mentioning

confidence: 96%

“…Both neuregulins and ErbBs are concentrated at the NMJ (Altiok et al, 1995;Goodearl et al, 1995;Jo et al, 1995;Moscoso et al, 1995;Sandrock et al, 1995). However, ectopic agrin alone can induce the synthesis and aggregation of f unctional adult subtype AChR channels (Jones et al, 1996(Jones et al, , 1997. One way in which agrin might induce AChR gene transcription via the neuregulin / ErbB pathway is by inducing the binding of a muscle-derived neuregulin to synaptic BL and by concentrating ErbB receptors in synaptic muscle membrane.…”

Section: Aggregation Of Erbb Receptorsmentioning

confidence: 99%

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Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers

Meier¹,

et al. 1997

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Neural agrin, in the absence of a nerve terminal, can induce the activity-resistant expression of acetylcholine receptor (AChR) subunit genes and the clustering of synapse-specific adult-type AChR channels in nonsynaptic regions of adult skeletal muscle fibers. Here we show that, when expression plasmids for neural agrin are injected into the extrasynaptic region of innervated muscle fibers, the following components of the postsynaptic apparatus are aggregated and colocalized with ectopic agrininduced AChR clusters: laminin-␤2, MuSK, phosphotyrosinecontaining proteins, ␤-dystroglycan, utrophin, and rapsyn. These components have been implicated to play a role in the differentiation of neuromuscular junctions. Furthermore, ErbB2 and ErbB3, which are thought to be involved in the regulation of neurally induced AChR subunit gene expression, were colocalized with agrin-induced AChR aggregates at ectopic nerve-free sites. The postsynaptic muscle membrane also contained a high concentration of voltage-gated Na ϩ channels as well as deep, basal lamina-containing invaginations comparable to the secondary synaptic folds of normal endplates. The ability to induce AChR aggregation in vivo was not observed in experiments with a muscle-specific agrin isoform. Thus, a motor neuron-specific agrin isoform is sufficient to induce a full ectopic postsynaptic apparatus in muscle fibers kept electrically active at their original endplate sites.

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Regulation and functional significance of utrophin expression at the mammalian neuromuscular synapse

Gramolini

Jasmin

2000

Microsc. Res. Tech.

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Duchenne muscular dystrophy (DMD) is caused by the absence of full‐length dystrophin molecules in skeletal muscle fibers. In normal muscle, dystrophin is found along the length of the sarcolemma where it links the intracellular actin cytoskeleton to the extracellular matrix, via the dystrophin‐associated protein (DAP) complex. Several years ago, an autosomal homologue to dystrophin, termed utrophin, was identified and shown to be expressed in a variety of tissues, including skeletal muscle. However, in contrast to the localization of dystrophin in extrajunctional regions of muscle fibers, utrophin preferentially accumulates at the postsynaptic membrane of the neuromuscular junction in both normal and DMD adult muscle fibers. Since it has recently been suggested that the upregulation of utrophin might functionally compensate for the lack of dystrophin in DMD, considerable interest is now directed toward the elucidation of the various regulatory mechanisms presiding over expression of utrophin in normal and dystrophic skeletal muscle fibers. In this review, we discuss some of the most recent data relevant to our understanding of the impact of myogenic differentiation and innervation on the expression and localization of utrophin in skeletal muscle fibers. Microsc. Res. Tech. 49:90–100, 2000. © 2000 Wiley‐Liss, Inc.

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Substrate-bound agrin induces expression of acetylcholine receptor epsilon-subunit gene in cultured mammalian muscle cells.

Cited by 80 publications

References 35 publications

Muscle and Neural Isoforms of Agrin Increase Utrophin Expression in Cultured Myotubes via a Transcriptional Regulatory Mechanism

Muscle and Neural Isoforms of Agrin Increase Utrophin Expression in Cultured Myotubes via a Transcriptional Regulatory Mechanism

Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers

Regulation and functional significance of utrophin expression at the mammalian neuromuscular synapse

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