Patterning of Muscle Acetylcholine Receptor Gene Expression in the Absence of Motor Innervation

Yang, Xia; Arber, Silvia; William, Christopher; Li, Li; Tanabe, Yukito; Jessell, Thomas M.; Birchmeier, Carmen; Burden, Steven J.

doi:10.1016/s0896-6273(01)00287-2

Cited by 443 publications

(500 citation statements)

References 53 publications

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“…AChR gene expression and AChR clusters are concentrated in the central region of skeletal muscle in the absence of innervation (Lin et al, 2001;Yang et al, 2001;Yang et al, 2000). This nerve-independent patterning of AChR expression, termed muscle prepatterning, is dependent upon MuSK (Lin et al, 2001;Yang et al, 2001), a receptor tyrosine kinase that is activated by Agrin and essential for neuromuscular synapse formation (DeChiara et al, 1996;Strochlic et al, 2005).…”

Section: Musk Expression Is Patterned In Muscle Lacking Motor Axonsmentioning

confidence: 99%

“…This nerve-independent patterning of AChR expression, termed muscle prepatterning, is dependent upon MuSK (Lin et al, 2001;Yang et al, 2001), a receptor tyrosine kinase that is activated by Agrin and essential for neuromuscular synapse formation (DeChiara et al, 1996;Strochlic et al, 2005). To determine whether MuSK itself is prepatterned in muscle lacking motor axons, we examined the pattern of MuSK expression in muscles from mice that lack motor axons.…”

Section: Musk Expression Is Patterned In Muscle Lacking Motor Axonsmentioning

confidence: 99%

“…To determine whether MuSK itself is prepatterned in muscle lacking motor axons, we examined the pattern of MuSK expression in muscles from mice that lack motor axons. Mice that lack motor neurons were generated by crossing HB9 cre mice, which express Cre recombinase selectively in developing motor neurons, with Isl2 loxP-stop-loxP-DTA mice, which, following Cre-mediated deletion of a translational stop sequence, express diphtheria toxin A (DTA) from the isl2 gene (Yang et al, 2001). In mice carrying both alleles, DTA is expressed in developing motor neurons, leading to death of motor neurons before they differentiate and extend axons into muscle (Yang et al, 2001).…”

Section: Musk Expression Is Patterned In Muscle Lacking Motor Axonsmentioning

confidence: 99%

“…In mice that lack DNA topoisomerase IIβ, motor axons fail to innervate diaphragm and limb muscles, yet AChR clusters are concentrated in the central region of these muscles (Yang et al, 2000). Subsequent studies, which examined the roles of Agrin and MuSK in nerveindependent muscle patterning, demonstrated that MuSK, but not Agrin is required to cluster AChRs in the central region of the muscle (Lin et al, 2001;Yang et al, 2001). This nerveindependent prepattern of AChR expression is then modified and sharpened by two neural signals: Agrin, which stabilizes AChR clusters, and acetylcholine (ACh), which extinguishes AChR clusters (Lin et al, 2005;Misgeld et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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MuSK controls where motor axons grow and form synapses

2007

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SummaryIt had long been thought that motor axons approach muscles that are regionally unspecialized and induce postsynaptic differentiation by releasing signals that focally initiate transcriptional and post-translational responses in muscle. This neuro-centric view of synapse formation, however, has been challenged by recent experiments, which showed that AChR clusters are concentrated in the central region of muscle independent of innervation. This nerve-independent prepattern of AChR expression requires MuSK, a receptor tyrosine kinase that is critical for synapse formation. How muscle prepatterning is established and whether motor axons recognize this prepattern are not known. Here, we show that MuSK itself is prepatterned in muscle and that high, ectopic MuSK expression is sufficient to promote ectopic motor axon growth and synapse formation, indicating that the muscle prepattern is recognized by motor axons and promotes synapse formation in the central region of developing mammalian muscle. Further, we provide evidence that early expression of MuSK in developing myotubes is sufficient to re-establish muscle prepatterning independent of the MuSK promoter. Moreover, we show that ectopic MuSK expression stimulates synapse formation in the absence of Agrin and rescues the neonatal lethality of agrin mutant mice, demonstrating that MuSK, independent of Agrin, is sufficient to direct presynaptic and postsynaptic differentiation. In contrast to a neuro-centric view for synapse formation, these data demonstrate that the postsynaptic cell can play a dominant role in regulating synapse formation.

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Section: Musk Expression Is Patterned In Muscle Lacking Motor Axonsmentioning

confidence: 99%

Section: Musk Expression Is Patterned In Muscle Lacking Motor Axonsmentioning

confidence: 99%

Section: Musk Expression Is Patterned In Muscle Lacking Motor Axonsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MuSK controls where motor axons grow and form synapses

2007

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“…All the nAChR subunit transcript levels are reduced to a similar extent in inputdeprived embryonic CG neurons, and intracellular protein levels for both ␣3-nAChRs and ␣7-nAChRs drop (Arenella et al, 1993;Brumwell et al, 2002;Kaiser et al, 2002). Interestingly, even a small amount of residual innervation is sufficient to restore detectable ␣7-nAChR clusters in the entire ganglion, suggesting that a powerful presynaptic soluble factor organizes receptor specialization (Kaiser et al, 2002) resembling the role of agin in muscle Yang et al, 2001). Lastly, the levels of other neuronal specific components, including synapse-related proteins that function at the presynaptic axon terminal, are not reduced by input deprivation (Arenella et al, 1993;Ikonomov et al, 1998).…”

Section: Inductive Effects Of Innervation On Nachr Expressionmentioning

confidence: 95%

Regulatory mechanisms that govern nicotinic synapse formation in neurons

et al. 2002

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Individual cholinoceptive neurons express high levels of different neuronal nicotinic acetylcholine receptor (nAChR) subtypes, and target them to the appropriate synaptic regions for proper function. This review focuses on the intercellular and intracellular processes that regulate nAChR expression in vertebrate peripheral nervous system (PNS) and central nervous system (CNS) neurons. Specifically, we discuss the cellular and molecular mechanisms that govern the induction and maintenance of nAChR expression-innervation, target tissue interactions, soluble factors, and activity. We define the regulatory principles of interneuronal nicotinic synapse differentiation that have emerged from these studies. We also discuss the molecular players that target nAChRs to the surface membrane and the interneuronal synapse.

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Postsynaptic Membranes at the Neuromuscular Junction: Molecular Organisation

Cartaud

Kordeli

Cartaud

2010

Encyclopedia of Life Sciences

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Accurate neurotransmission between motor nerve and muscle fibres at the vertebrate cholinergic neuromuscular junction (NMJ) depends on the differentiation of highly specialised structures both pre‐ and postsynaptically. The accumulation of nicotinic acetylcholine receptors ( AChR s) and voltage‐gated sodium channels represents the hallmark of postsynaptic membrane differentiation. Several synaptic organising proteins are required for the aggregation of postsynaptic AChR s. The muscle‐specific receptor tyrosine kinase (MuSK) provides a structural scaffold necessary to initiate aggregates of postsynaptic molecules. Agrin – a nerve‐derived extracellular matrix glycoprotein – is required for AChR clustering probably by activating MuSK activity. Rapsyn – the AChR ‐associated peripheral protein acting downstream of agrin –MuSK signalling – is essential for AChR clustering. These proteins, together with a wealth of other components of the synapse, cooperate in multiple ways to play both structural and signalling roles in synaptic differentiation. Synaptopathies of the NMJ result from mutations in several key players of synaptic differentiation. Key Concepts: Efficient communication between neurons or between neurons and their targets requires the enrichment of synaptic proteins, in particular, ligand‐gated ion channels at postsynaptic sites. The NMJ represents a particularly striking example of accumulation of nicotinic acetylcholine receptors in the postsynaptic membrane and is an ideal model to study receptor clustering. Formation and maintenance of the postsynaptic membrane is a complex mechanism involving synaptic organising molecules derived both from nerve and muscle. The muscle tyrosine kinase, MuSK, is the master organiser of the NMJ capable to initiate clustering of postsynaptic components, even in the absence of neuronal cues. Mutations in several components of the postsynaptic membrane (not only in AChR subunits genes but also in agrin, ColQ, DOK‐7, laminin, MuSK, rapsyn, etc.) result in severe dysfunction of the NMJ: the congenital myasthenic syndromes.

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Patterning of Muscle Acetylcholine Receptor Gene Expression in the Absence of Motor Innervation

Cited by 443 publications

References 53 publications

MuSK controls where motor axons grow and form synapses

MuSK controls where motor axons grow and form synapses

Regulatory mechanisms that govern nicotinic synapse formation in neurons

Postsynaptic Membranes at the Neuromuscular Junction: Molecular Organisation

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