The Ets transcription factor GABP is required for postsynaptic differentiation in vivo.
At chemical synapses, neurotransmitter receptors are concentrated in the postsynaptic membrane. During the development of the neuromuscular junction, motor neurons induce aggregation of acetylcholine receptors (AChRs) underneath the nerve terminal by the redistribution of existing AChRs and preferential transcription of the AChR subunit genes in subsynaptic myonuclei. Neural agrin, when expressed in nonsynaptic regions of muscle fibers in vivo, activates both mechanisms resulting in the assembly of a fully functional postsynaptic apparatus. Several lines of evidence indicate that synaptic transcription of AChR genes is primarily dependent on a promoter element called N-box. The Ets-related transcription factor growth-associated binding protein (GABP) binds to this motif and has thus been suggested to regulate synaptic gene expression. Here, we assessed the role of GABP in synaptic gene expression and in the formation of postsynaptic specializations in vivo by perturbing its function during postsynaptic differentiation induced by neural agrin. We find that neural agrin-mediated activation of the AChR epsilon subunit promoter is abolished by the inhibition of GABP function. Importantly, the number of AChR aggregates formed in response to neural agrin was strongly reduced. Moreover, aggregates of acetylcholine esterase and utrophin, two additional components of the postsynaptic apparatus, were also reduced. Together, these results are the first direct in vivo evidence that GABP regulates synapse-specific gene expression at the neuromuscular junction and that GABP is required for the formation of a functional postsynaptic apparatus.
Department of Pharmacology/Neurobiology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
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Briguet
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Ruegg
D000110:Acetylcholinesterase / Q000378:metabolism; D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051268:GA-Binding Protein Transcription Factor; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000196:embryology* / Q000201:enzymology / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*; D013570:Synaptic Membranes / Q000201:enzymology* / Q000648:ultrastructure; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D049411:Utrophin
D018171:Agrin; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; D008565:Membrane Proteins; D011950:Receptors, Cholinergic; D014157:Transcription Factors; D049411:Utrophin; D000110:Acetylcholinesterase