The Ets Transcription Factor GABP Is Required for Postsynaptic Differentiation In Vivo

Abstract

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.

Phosphorylation-Elicited Quaternary Changes of GA Binding Protein in Transcriptional Activation

“…In agreement with previous reports, we show that the GABP complex is located exclusively in the nucleus (6,45). However, our in vitro approach with living C2C12 cells allowed us to determine that fluorescent GABP is entirely excluded from the nucleoli.…”

Development of a human mitochondria-focused cDNA microarray (hMitChip) and validation in skeletal muscle cells: implications for pharmaco- and mitogenomics

“…41 There is evidence that GABP functions as a transcriptional activator for synaptic genes, including nicotinic acetylcholine receptor, acetylcholine esterase and utrophin. 42,43 Thus, downregulation of the GABPA gene in skeletal myocytes after long-term exposure to Dex, as shown in our study, may indirectly reduce the transcription rate of these synaptic genes, potentially interfering with the nerve influx to the muscle. This hypothesis remains to be tested.…”

PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy

“…NRG-1 is sufficient to induce transcript levels of many NMJ genes, although recent reports showed that NRG-1 signaling is not required for NMJ formation in vivo (Escher et al 2005;Jaworski and Burden 2006). Importantly, agrin and NRG-1 signaling both converge on the transcription factor GABP (Briguet and Ruegg 2000). The two GABP subunits, GABPA and GABPB, are subsequently phosphorylated and bind to N-box elements in the promoters of NMJ genes.…”