Expression of mutant Ets protein at the neuromuscular synapse causes alterations in morphology and gene expression

d’Exaerde, Alban de Kerchove; Cartaud, Jean; Ravel‐Chapuis, Aymeric; Seroz, Thierry; Pasteau, Fabien; Angus, Lindsay; Jasmin, Bernard J.; Changeux, Jean‐Pierre; Schaeffer, Laurent

doi:10.1093/embo-reports/kvf220

Cited by 35 publications

(9 citation statements)

References 32 publications

(41 reference statements)

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“…N-box-dependent synaptic expression is stimulated by agrin and neuregulin, which triggers the mitogen-activated protein kinase and Jun N-terminal kinase signaling pathways to ultimately allow activation by the N-box binding Ets transcription factor, GABP (reviewed in reference 41). However, the level of some synaptic genes, including rapsyn, was not perturbed in the muscles of mutant mice expressing a skeletal muscle-targeted, general Ets dominant-negative mutant (9). This suggests that rapsyn expression is controlled by a mechanism that does not involve the Ets transcription factor and N box and that other synapse-specific mechanisms are likely to control the expression of rapsyn.…”

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confidence: 94%

Regulation of the Rapsyn Promoter by Kaiso and δ-Catenin

Rodova

Kelly

VanSaun

et al. 2004

Molecular and Cellular Biology

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Rapsyn is a synapse-specific protein that is required for clustering acetylcholine receptors at the neuromuscular junction. Analysis of the rapsyn promoter revealed a consensus site for the transcription factor Kaiso within a region that is mutated in a subset of patients with congenital myasthenic syndrome. Kaiso is a POZzinc finger family transcription factor which recognizes the specific core consensus sequence CTGCNA (where N is any nucleotide). Previously, the only known binding partner for Kaiso was the cell adhesion cofactor, p120 catenin. Here we show that ␦-catenin, a brain-specific member of the p120 catenin subfamily, forms a complex with Kaiso. Antibodies against Kaiso and ␦-catenin recognize proteins in the nuclei of C2C12 myocytes and at the postsynaptic domain of the mouse neuromuscular junction. Endogenous Kaiso in C2C12 cells coprecipitates with the rapsyn promoter in vivo as shown by chromatin immunoprecipitation assay. Minimal promoter assays demonstrated that the rapsyn promoter can be activated by Kaiso and ␦-catenin; this activation is apparently muscle specific. These results provide the first experimental evidence that rapsyn is a direct sequence-specific target of Kaiso and ␦-catenin. We propose a new model of synapse-specific transcription that involves the interaction of Kaiso, ␦-catenin, and myogenic transcription factors at the neuromuscular junction.

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confidence: 94%

Regulation of the Rapsyn Promoter by Kaiso and δ-Catenin

Rodova

Kelly

VanSaun

et al. 2004

Molecular and Cellular Biology

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“…This indicates that other transcription factors, including other ETS proteins, expressed in skeletal muscle cells may, to some degree, compensate for loss of Gabp␣ expression. This is supported by reduced levels of Utrophin, AChRε, and AChE in the vastus lateralis of mice expressing a dominant-negative ETS (comprised of the ETS DNA binding domain) protein in skeletal muscle (7). In addition, although our data showing decreased AChRε expression in the absence of Gabp function agree with those of Briguet and Ruegg (1), an impairment in AChR clustering was also observed following in vivo injection of a Gabp␤ dominant-negative construct into rat soleus muscle fibers (1), suggesting that the milder phenotype observed in this study may be partly explained by the ability of Gabp␤ to partner with another transcription factor.…”

Section: Discussionmentioning

confidence: 93%

“…Skeletal-muscle-specific, ETS dominant-negative mice exhibit muscles with small AChR patches and disorganized postsynaptic junctional folds (7). However, the ETS factor responsible for this phenotype was not identified.…”

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confidence: 99%

Targeting of the ETS Factor Gabpα Disrupts Neuromuscular Junction Synaptic Function

O'leary

Noakes

Lavidis

et al. 2007

Molecular and Cellular Biology

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The GA-binding protein (GABP) transcription factor has been shown in vitro to regulate the expression of the neuromuscular proteins utrophin, acetylcholine esterase, and acetylcholine receptor subunits ␦ and through the N-box promoter motif (5-CCGGAA-3), but its in vivo function remains unknown. A single point mutation within the N-box of the gene encoding the acetylcholine receptor subunit has been identified in several patients suffering from postsynaptic congenital myasthenic syndrome, implicating the GA-binding protein in neuromuscular function and disease. Since conventional gene targeting results in an embryonic-lethal phenotype, we used conditional targeting to investigate the role of GABP␣ in neuromuscular junction and skeletal muscle development. The diaphragm and soleus muscles from mutant mice display alterations in morphology and distribution of acetylcholine receptor clusters at the neuromuscular junction and neurotransmission properties consistent with reduced receptor function. Furthermore, we confirmed decreased expression of the acetylcholine receptor subunit and increased expression of the ␥ subunit in skeletal muscle tissues. Therefore, the GABP transcription factor aids in the structural formation and function of neuromuscular junctions by regulating the expression of postsynaptic genes.

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“…Mutation of the intronic proximal N‐box at position +755 bp (mouse equivalent +822 bp) eliminated synapse‐specific expression of AChE in rat muscle, whereas the distal N‐box at position +827 bp (rat equivalent of mouse +890 bp) was unnecessary for the response. Overexpression of a dominant negative GABP mouse transgene resulted in a 65% decrease in AChE mRNA in innervated muscle (de Kerchove D'Exaerde et al . 2002), suggesting that GABP functionally interacts with N‐box sites during synaptic expression.…”

Section: Discussionmentioning

confidence: 99%

The regulation of acetylcholinesterase by cis‐elements within intron I in cultured contracting myotubes

Cohen

Randall

2006

Journal of Neurochemistry

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The onset of spontaneous contraction in rat primary muscle cultures coincides with an increase in acetylcholinesterase (AChE) activity. In order to establish whether contractile activity modulates the rate of AChE transcript synthesis, and what elements of the gene are determinant, we examined the promoter and intron I in contracting muscle cultures. Ache genomic fragments attached to a luciferase reporter were transfected into muscle cultures that were either electrically stimulated or paralyzed with tetrodotoxin to enhance or inhibit contractions, respectively. Cultures transfected with intron I-containing constructs showed a 2-fold increase in luciferase activity following electrical stimulation, compared to tetrodotoxin treatment, suggesting that this region contains elements responding to contractile activity. Deleting a 780 bp distal region within intron I, containing an N-box element at +890 bp, or introducing a 2-bp mutation within its core sequence, eliminated the contraction-induced response. In contrast, mutating an N-box element at +822 bp had no effect on the response. Furthermore, co-transfecting a dominant negative GA-binding protein (GABP), a transcription factor known to selectively bind N-box elements, reduced the stimulation-mediated increase. Our results suggest that the N-box within intron I at +890 bp is a regulatory element important in the transcriptional response of Ache to contractile activity in muscle.

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Expression of mutant Ets protein at the neuromuscular synapse causes alterations in morphology and gene expression

Cited by 35 publications

References 32 publications

Regulation of the Rapsyn Promoter by Kaiso and δ-Catenin

Regulation of the Rapsyn Promoter by Kaiso and δ-Catenin

Targeting of the ETS Factor Gabpα Disrupts Neuromuscular Junction Synaptic Function

The regulation of acetylcholinesterase by cis‐elements within intron I in cultured contracting myotubes

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