Targeting Transcription to the Neuromuscular Synapse

Schaeffer, Laurent; d’Exaerde, Alban de Kerchove; Changeux, Jean‐Pierre

doi:10.1016/s0896-6273(01)00353-1

Cited by 194 publications

(172 citation statements)

References 47 publications

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“…It had long been thought that motor axons approach a muscle that is regionally unspecialized and induce postsynaptic differentiation by releasing signals that focally initiate transcriptional and post-translational responses in the muscle Pettigrew, 1974, 1976;Burden, 1998;Kandel et al, 2000;Sanes and Lichtman, 2001;Schaeffer et al, 2001). These studies implicated motor neuron-derived Agrin, a glycosylated proteoglycan, as the critical neural signal for inducing postsynaptic differentiation and the muscle-specific receptor tyrosine kinase, MuSK, a component of the Agrin receptor, as the transducer for clustering AChRs and activating AChR gene expression at synaptic sites (Burden, 1998;Glass et al, 1996a;Glass et al, 1996b;Glass and Yancopoulos, 1997;Sanes and Lichtman, 2001;Schaeffer et al, 2001;Valenzuela et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…These studies implicated motor neuron-derived Agrin, a glycosylated proteoglycan, as the critical neural signal for inducing postsynaptic differentiation and the muscle-specific receptor tyrosine kinase, MuSK, a component of the Agrin receptor, as the transducer for clustering AChRs and activating AChR gene expression at synaptic sites (Burden, 1998;Glass et al, 1996a;Glass et al, 1996b;Glass and Yancopoulos, 1997;Sanes and Lichtman, 2001;Schaeffer et al, 2001;Valenzuela et al, 1995). This neuro-centric view of neuromuscular synapse formation, however, has been challenged by recent experiments, which showed that mammalian muscle is spatially patterned independent of innervation.…”

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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MuSK controls where motor axons grow and form synapses

2007

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“…Such a wealth of transcriptional behaviors have to be encoded in the promoters that control the expression of the subunit genes (see Duclert and Changeux (1995) and Schaeffer et al (2001) for model system of the motor endplate and Bessis et al (1995) for the neuronal nAChRs). However, a given stretch of DNA can only encrypt a limited amount of transcriptional information.…”

Section: Promoters and Regulation Of Expressionmentioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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“…Indeed, these genes share some features of transcriptional control. For example, the nACHR subunit and utrophin-A promoter N-box play a critical role in regulating expression levels and more importantly in restricting expression to the NMJ (Schaeffer et al, 2001). We and others (Gramolini et al, 1999a;Khurana et al, 1999) have shown that the nerve-derived growth factor heregulin (HRG) causes a N-box-mediated increase in utrophin-A promoter activity via extracellular signal-regulated kinase-dependent activation of the Ets-related transcription factor complex GABP␣/␤, in a manner similar to that noted in the nACHR␦ and nACHR subunit promoters (Falls et al, 1993;Koike et al, 1995;Sapru et al, 1998; This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06 -12-1069) on May 16, 2007. 1998).…”

Section: Introductionmentioning

confidence: 99%

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

Perkins

Basu

Budak

et al. 2007

MBoC

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Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABP␣/␤ to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest "repressing repressors" as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle. INTRODUCTIONDuchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by gene mutations leading to qualitative or quantitative disturbances in dystrophin expression (Hoffman et al., 1987). Dystrophin-related protein or utrophin is considered the autosomal homologue of dystrophin, because it shares extensive sequence homology as well as its size and abundance in muscle (Love et al., 1989;Khurana et al., 1990;Tinsley et al., 1992). Utrophin and dystrophin also share functional properties such as the ability to associate with the dystroglycan complex and bind F-actin (Matsumura et al., 1992;Winder and Kendrick, 1995;Rybakova et al., 2002). Direct evidence for the ability of utrophin to functionally substitute comes from experiments demonstrating that utrophin overexpression driven either by transgenic means Rafael et al., 1998;Tinsley et al., 1998;Fisher et al., 2001) or viral vectors (Gilbert et al., 1999;Wakefield et al., 2000;Cerletti et al., 2003) can rescue dystrophin-deficient muscle. Despite these functional similarities, dystrophin and utrophin exhibit distinct localization in normal adult tissues.Perinatally, utrophin is expressed throughout the sarcolemma, however, its expression declines as that of dystrophin increases (Khurana et al., 1991;Clerk et al., 1993), leading to its spatially restricted expression at neuromuscular and myotendinous junctions (NMJs and MTJs, respectively) of adult myofibers. These features and relevance toward a therapy for DMD provide a powerful impetus for b...

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Targeting Transcription to the Neuromuscular Synapse

Cited by 194 publications

References 47 publications

MuSK controls where motor axons grow and form synapses

MuSK controls where motor axons grow and form synapses

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

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