Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse

Lin, Weichun; Burgess, Robert W.; Dominguez, Bertha; Pfaff, Samuel L.; Sanes, Joshua R.; Lee, Kuo Fen

doi:10.1038/35074025

Cited by 499 publications

(436 citation statements)

References 43 publications

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“…subunit transcription remains relatively unchanged, in contrast to our previous demonstration that Cdk5 is required for NRG͞ErbB-mediated regulation of AChR subunit transcription in myotube culture (5). The differential effects of Cdk5͞NRG signaling on AChR transcription in vitro and in vivo might be due to the presence of redundant signaling mechanism in muscle, i.e., agrin͞MuSK (16,34,35).…”

Section: Discussioncontrasting

confidence: 49%

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

et al. 2005

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

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Cyclin-dependent kinase (Cdk)5 is a key regulator of neural development. We have previously demonstrated that Cdk5͞p35 are localized to the postsynaptic muscle and are implicated in the regulation of neuregulin͞ErbB signaling in myotube culture. To further elucidate whether Cdk5 activity contributes to neuromuscular junction (NMJ) development in vivo, the NMJ of Cdk5 ؊/؊ mice was examined. Consistent with our previous demonstration that Cdk5 phosphorylates ErbB2͞3 to regulate its tyrosine phosphorylation, we report here that the phosphorylation of ErbB2 and ErbB3 and the ErbB2 kinase activity are reduced in Cdk5-deficient muscle. In addition, Cdk5 ؊/؊ mice also display morphological abnormalities at the NMJ pre-and postsynaptically. Whereas the outgrowth of the main nerve trunk is grossly normal, the intramuscular nerve projections exhibit profuse and anomalous branching patterns in the Cdk5 ؊/؊ embryos. The central band of acetylcholine receptor (AChR) clusters is also wider in Cdk5 ؊/؊ diaphragms, together with the absence of S100 immunoreactivity along the phrenic nerve during late embryonic stages. Moreover, we unexpectedly discovered that the agrin-induced formation of large AChR clusters is significantly increased in primary muscle cultures prepared from Cdk5-null mice and in C2C12 myotubes when Cdk5 activity was suppressed. These abnormalities are accompanied by elevated frequency of miniature endplate potentials in Cdk5-null diaphragm. Taken together, our findings reveal the essential role of Cdk5 in regulating the development of motor axons and neuromuscular synapses in vivo.agrin ͉ Cdk5 ͉ ErbB receptor ͉ neuromuscular junction

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Section: Discussioncontrasting

confidence: 49%

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

et al. 2005

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

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“…In the absence of innervation, AChR genes are expressed preferentially in the central region of muscle (13)(14)(15). These findings suggest that muscle prepatterning may establish a preferred region for motor innervation.…”

Section: Cd24 Is Expressed Preferentially By Myofiber Synaptic Nucleimentioning

confidence: 63%

CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission

Jevsek

Jaworski

Polo‐Parada

et al. 2006

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

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The genes encoding several synaptic proteins, including acetylcholine receptors, acetylcholinesterase, and the muscle-specific kinase, MuSK, are expressed selectively by a small number of myofiber nuclei positioned near the synaptic site. Genetic analysis of mutant mice suggests that additional genes, expressed selectively by synaptic nuclei, might encode muscle-derived retrograde signals that regulate the differentiation of motor axon terminals. To identify candidate retrograde signals, we used a microarray screen to identify genes that are preferentially expressed in the synaptic region of muscle, and we analyzed one such gene, CD24, further. We show that CD24, which encodes a small, variably and highly glycosylated, glycosylphosphatidylinositol (GPI)-linked protein, is expressed preferentially by myofiber synaptic nuclei in embryonic and adult muscle, and that CD24 expression is restricted to the central region of muscle independent of innervation. Moreover, we show that CD24 has a role in presynaptic differentiation, because synaptic transmission is depressed and fails entirely, in a cyclical manner, after repetitive stimulation of motor axons in CD24 mutant mice. These deficits in synaptic transmission, which are accompanied by aberrant stimulus-dependent uptake of AM1-43 from axons, indicate that CD24 is required for normal presynaptic maturation and function. Because CD24 is also expressed in some neurons, additional experiments will be required to determine whether pre-or postsynaptic CD24 mediates these effects on presynaptic development and function.heat-stable antigen ͉ neuromuscular synapses ͉ P-selectin ͉ synapse-specific transcription N early one dozen genes, including those encoding acetylcholine receptors (AChRs), acetylcholinesterase (AChE), muscle-specific kinase (MuSK), and utrophin, are expressed selectively by a small number of myofiber nuclei positioned near the synaptic site (1-5). This pattern of gene expression depends on MuSK, a muscle-specific receptor tyrosine kinase that is activated by neurally derived agrin, because ''synapse-specific'' genes are expressed uniformly in muscle from MuSK mutant mice (6). In addition, presynaptic differentiation is MuSKdependent, because motor axons fail to stop and differentiate in agrin or MuSK mutant mice (6, 7). Because MuSK is required for synapse-specific transcription and presynaptic differentiation, these findings raise the possibility that muscle-derived signals, which cause motor axons to stop growing and differentiate, may be expressed preferentially by myofiber synaptic nuclei.Among the known synapse-specific genes, AChR, AChE, MuSK, NCAM, and S-laminin encode for cell surface proteins, suggesting that these proteins could, in principle, function as retrograde signals (1-3, 5, 8). It seems likely, however, that additional genes, encoding cell surface proteins, are transcribed preferentially by myofiber synaptic nuclei. In mammalian muscle, neuromuscular synapses are confined to a narrow zone, near the center of the muscle. As such, the syn...

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“…Basic helix-loop-helix myogenic factors expressed in early myotubes induce the expression of acetylcholine receptor (AChR) subunits that compose the heteropentameric ligand-gated ion channel. It was observed more than two decades ago (7), and has more recently been studied in greater detail (8,9), that AChRs form clusters before innervation or when innervation is prevented ( Fig. 1 A).…”

mentioning

confidence: 99%

“…1 A). The formation of these prepatterned AChR clusters requires the musclespecific receptor tyrosine kinase MuSK and the AChR-scaffolding molecule rapsyn (9). Upon innervation, the nervereleased splice version of the large heparansulfate proteoglycan agrin aggregates and maintains postsynaptic AChR clusters underneath the nerve terminal (10).…”

mentioning

confidence: 99%

Organization of synaptic myonuclei by Syne proteins and their role during the formation of the nerve–muscle synapse

Rüegg

2005

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

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Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse

Cited by 499 publications

References 43 publications

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice

CD24 is expressed by myofiber synaptic nuclei and regulates synaptic transmission

Organization of synaptic myonuclei by Syne proteins and their role during the formation of the nerve–muscle synapse

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