Neuregulins: primary or secondary signals for the control of synapse-specific gene expression

The selective transcription of acetylcholine receptor (AChR) subunit genes in synaptic myonuclei leads to the accumulation of AChR subunit mRNAs at the neuromuscular junction (NMJ). This mechanism contributes to the concentration of AChRs at the postsynaptic sarcolemma, and its physiological significance is underscored by the cases of human congenital myasthenias caused by mutation in a cis-regulatory element of the AChRepsilon-subunit promoter, which is necessary for its synaptic expression. The signal(s) that drives synapse-specific expression is unknown but neuregulin-1 (Nrg-1), a group of growth-factor-like polypeptides encoded by the nrg-1 gene, has been a favorite candidate. Nrg-1 was originally thought as a nerve-derived factor, acting in parallel to pathways controlling AChR clustering at the synapse ( i.e. agrin signaling). However, recent work suggests that Nrg-1 may actually be a muscle-derived signal that is concentrated at the NMJ, together with its receptors, by agrin and that acts as a secondary, downstream signal to enhance synapse-specific AChR transcription. Here, I review studies for and against Nrg-1 as a secondary signal driving synapse-specific expression at the NMJ. In addition, I briefly present new evidence that raise the possibility that Nrgs encoded by the ngr-1 -related gene nrg-2 might have a role controlling AChR expression.