Chapter 32 Agrin

Magill, Catherine; Reist, Noreen E.; Fallen, Justin R.; Nitkin, Ralph; Wallace, Bruce G.; McMahan, Uel J.

doi:10.1016/s0079-6123(08)61840-3

Cited by 15 publications

(14 citation statements)

References 12 publications

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“…The levels of receptor mRNAs begin to accumulate significantly after 1 day of denervation, and by day 7 they are =70-fold higher than in innervated muscle. The increases in myogenin, MyoD, and nAChR transcripts after denervation are specific because the levels of a-actin mRNA remained constant (24,25) and by the "electrical activity" resulting from muscle depolarization during neuromuscular transmission (26). To test if electrical activity per se downregulates the levels of myogenin and MyoD transcripts, electrodes were implanted into the hindlimbs of rats immediately after denervation and electrically stimulated (see Materials and Methods) for 6 or 10 days.…”

Section: Resultsmentioning

confidence: 99%

“…Innervation has a dual component; it elicits electrical activity that regulates muscle properties (26) and provides chemical cues that may restrict the spatial distribution of molecules to the neuromuscular junction (24,25). For example, the expression of nAChR mRNAs at extrajunctional regions of the muscle decrease dramatically during innervation, whereas the transcripts that remain are enriched at synaptic nuclei (42)(43)(44)(45).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the fact that these myogenic factors can autoregulate their own expression (46) could account for the observation that nAChR subunit mRNAs continue to be expressed preferentially in the junctional region even after denervation (45). Alternatively, longerlasting signals that remain in the basal lamina after denervation (25) could regulate the expression of receptors, and possibly the myogenic factors. Further experiments will be needed to dissect the effects of trophic factors and electrical activity on the regulation of myogenin and MyoD expression.…”

Section: Resultsmentioning

confidence: 99%

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Myogenin and MyoD join a family of skeletal muscle genes regulated by electrical activity.

Eftimie

Brenner

Buonanno

1991

Proc. Natl. Acad. Sci. U.S.A.

281

235

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Myogenin and MyoD are proteins that bind to the regulatory regions of a battery of skeletal muscle genes and can activate their transcription during muscle differentiation. We have recently found that both proteins interact with the enhancer of the nicotinic acetylcholine receptor (nAChR) a subunit, a gene that is regulated by innervation. This observation prompted us to study if myogenin and MyoD transcript levels are also regulated by skeletal muscle innervation. Using Northern blot analysis, we found that MyoD and myogenin mRNA levels begin to decline at embryonic day 17 and attain adult levels in muscle of newborn and 3-week-old mice, respectively. In contrast, nAChR mRNAs are highest in newborn and 1-week-old mouse muscle and decline thereafter to reach adult levels in 3-week-old mice. To determine if the downregulation of myogenin and MyoD mRNA levels during development is due to innervation, we quantitated message levels in adult calf muscles after denervation. We found that in denervated muscle myogenin and MyoD mRNAs reach levels that are approximately 40-and 15-fold higher than those found in innervated muscle. Myogenin mRNAs begin to accumulate rapidly between 8 and 16 hr after denervation, and MyoD transcripts levels begin to increase sharply between 16 hr and 1 day after denervation. The increases in myogenin and MyoD mRNA levels precede the rapid accumulation of nAChR a-subunit transcripts; receptor mRNAs begin to accumulate significantiy after 1 day of denervation. The effects of denervation are specific because skeletal a-actin mRNA levels are not affected by denervation. In addition, we found that the repression of myogenin and MyoD expression by innervation is due, at least in part, to "electrical activity." Direct stimulation of soleus muscle with extracellular electrodes repressed the increase of myogenin and MyoD transcripts after denervation by 4-to 3-fold, respectively. In view of these results, it is interesting to speculate that myogenin and/or MyoD may regulate a repertoire ofskeletal muscle genes that are down-regulated by electrical activity.Development of skeletal muscle cells is characterized by a series ofevents that include commitment, differentiation, and maturation. Myoblasts arise from the commitment of pluripotential mesodermal cells to the myogenic lineage. The myoblasts proliferate and later differentiate and fuse to form multinucleated embryonic myotubes. Differentiation is characterized by the transcriptional activation of a battery of muscle-specific genes coding for metabolic enzymes, contractile proteins, ion channels, and neurotransmitter receptors (1-4

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Myogenin and MyoD join a family of skeletal muscle genes regulated by electrical activity.

Eftimie

Brenner

Buonanno

1991

Proc. Natl. Acad. Sci. U.S.A.

281

235

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“…Moreover, mAbs directed against agrin stain molecules in the synaptic cleft of Torpedo neuromuscular junctions (6). Together, these findings have given rise to the "agrin hypothesis": the AChR-and AChE-aggregating molecules in the synaptic basal lamina at the neuromuscular junction are similar to agrin (6,12,31).…”

mentioning

confidence: 95%

Agrin-like molecules at synaptic sites in normal, denervated, and damaged skeletal muscles.

Reist

Magill

McMahan

1987

The Journal of Cell Biology

170

138

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Abstract. Several lines of evidence have led to the hypothesis that agrin, a protein extracted from the electric organ of Torpedo, is similar to the molecules in the synaptic cleft basal lamina at the neuromuscular junction that direct the formation of acetylcholine receptor and acetylcholinesterase aggregates on regenerating myofibers. One such finding is that monoclonal antibodies against agrin stain molecules concentrated in the synaptic cleft of neuromuscular junctions in rays. In the studies described here we made additional monoclonal antibodies against agrin and used them to extend our knowledge of agrin-like molecules at the neuromuscular junction. We found that antiagrin antibodies intensely stained the synaptic cleft of frog and chicken as well as that of rays, that denervation of frog muscle resulted in a reduction in staining at the neuromuscular junction, and that the synaptic basal lamina in frog could be stained weeks after degeneration of all cellul~ir components of the neuromuscular junction. We also describe anti-agrin staining in nonjunctional regions of muscle. We conclude the following: (a) agrin-like molecules are likely to be common to all vertebrate neuromuscular junctions; (b) the long-term maintenance of such molecules at the junction is nerve dependent; (c) the molecules are, indeed, a component of the synaptic basal lamina; and (d) they, like the molecules that direct the formation of receptor and esterase aggregates on regenerating myofibers, remain associated with the synaptic basal lamina after muscle damage.

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“…Agrin, a single-gene-encoded heparan sulfate proteoglycan of ϳ220 kDa, participates in nerve-muscle synaptic biogenesis through induction of acetylcholine receptor aggregation at postsynaptic sites, thereby generating a junction (Magill et al, 1987;Rupp et al, 1992). The word "agrin" (Greek agreirein) denotes its ability to bring diverse molecules together to perform specific functions.…”

Section: Introductionmentioning

confidence: 99%

Agrin Downregulation Induced by Nerve Injury Contributes to Neuropathic Pain

Bazán¹

2010

J. Neurosci.

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The elusiveness of neuropathic pain mechanisms is a major impediment in developing effective clinical treatments. Here we show that peripheral nerve injury decreased agrin expression in the ipsilateral spinal dorsal horn of rats displaying tactile allodynia. SCP1, an acetaminophen analog, suppressed allodynia and promoted agrin upregulation. Preemptive treatment with SCP1 also upregulated agrin, thereby preventing neuropathic pain development. Expression of 50 kDa agrin delivered by adeno-associated virus into the dorsal horn also suppressed allodynia and hyperalgesia. Allodynia suppression was a consequence of serine residue 896/897 phosphorylation of NMDA receptor NR1 subunits in the GABA interneurons of the dorsal horn. Agrin silencing by small interference RNA, administered with either AAV-Ag50 vector or SCP1, blocked allodynia suppression, agrin upregulation, and NR1 phosphorylation. In conclusion, 50 kDa agrin modulates neuropathic pain through NR1 phosphorylation in GABA neurons. This mechanism may open new approaches for treating not only neuropathic pain, but also epilepsy, tremors, and spasticity.

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Chapter 32 Agrin

Cited by 15 publications

References 12 publications

Myogenin and MyoD join a family of skeletal muscle genes regulated by electrical activity.

Myogenin and MyoD join a family of skeletal muscle genes regulated by electrical activity.

Agrin-like molecules at synaptic sites in normal, denervated, and damaged skeletal muscles.

Agrin Downregulation Induced by Nerve Injury Contributes to Neuropathic Pain

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