Regulation of the acetylcholine receptor ϵ subunit gene by recombinant ARIA: An in vitro model for transynaptic gene regulation

Structural specialization of the postsynaptic skeletal muscle membrane is in part mediated by the motor neuron-induced transcriptional regulation of synaptic muscle nuclei. ARIA, a factor that stimulates production of acetylcholine receptors (AChRs), is a candidate signaling molecule for such regulation. Here we examine the transynaptic inducing potential of this polypeptide factor. ARIA immunoreactivity is detectable at synaptic sites in vivo. In vitro, recombinant heregulin β1 (rHRGβ1), the human homolog of ARIA, induces expression of the AChR ε{lunate} gene, the subunit most sensitive to synaptic input. The inducing property of rHRGβ1 is demonstrated most dramatically in primary muscle culturesfrom transgenic mice bearing an ε{lunate} promoter-nuclear lacZ reporter transgene. Transient transfection experiments using the Sol 8 muscle cell line indicate that sequences that confer responsiveness to ARIA are located within a 150 by ε{lunate} subunit promoter region and are E box-independent. These results suggest that ARIA performs a vital role by directing spatially restricted gene expression at the neuromuscular junction.