The ets transcription factor GABP is required for postsynaptic differentiation in vivo

At chemical synapses, neurotransmitter receptors are concentrated in the po stsynaptic membrane. During the development of the neuromuscular junction, motor neurons induce aggregation of acetylcholine receptors (AChRs) underne ath the nerve terminal by the redistribution of existing AChRs and preferen tial transcription of the AChR subunit genes in subsynaptic myonuclei. Neur al agrin, when expressed in nonsynaptic regions of muscle fibers in vivo, a ctivates both mechanisms resulting in the assembly of a fully functional po stsynaptic apparatus. Several lines of evidence indicate that synaptic tran scription of AChR genes is primarily dependent on a promoter element called N-box. The Ets-related transcription factor growth-associated binding prot ein (GABP) binds to this motif and has thus been suggested to regulate syna ptic gene expression. Here, we assessed the role of GABP in synaptic gene e xpression and in the formation of postsynaptic specializations in vivo by p erturbing its function during postsynaptic differentiation induced by neura l agrin. We find that neural agrin-mediated activation of the AChR epsilon subunit promoter is abolished by the inhibition of GABP function. Important ly, the number of AChR aggregates formed in response to neural agrin was st rongly reduced. Moreover, aggregates of acetylcholine esterase and utrophin , two additional components of the postsynaptic apparatus, were also reduce d. Together, these results are the first direct in vivo evidence that GABP regulates synapse-specific gene expression at the neuromuscular junction an d that GABP is required for the formation of a functional postsynaptic appa ratus.