REGULATION OF THE ACETYLCHOLINE-RECEPTOR EPSILON-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 regul ation of synaptic muscle nuclei. ARIA, a factor that stimulates produc tion of acetylcholine receptors (AChRs), is a candidate signaling mole cule for such regulation. Here we examine the transynaptic inducing po tential of this polypeptide factor. ARIA immunoreactivity is detectabl e at synaptic sites in vivo. In vitro, recombinant heregulin beta 1 (r HRG beta 1), the human homolog of ARIA, induces expression of the AChR epsilon gene, the subunit most sensitive to synaptic input. The induc ing property of rHRG beta 1 is demonstrated most dramatically in prima ry muscle cultures from transgenic mice bearing an epsilon promoter-nu clear lacZ reporter transgene. transient transfection experiment; usin g the Sol 8 muscle cell line indicate that sequences that confer respo nsiveness to ARIA are located within a 150 bp epsilon subunit promoter region and are, E box-independent. These results suggest that ARIA pe rforms a vital role by directing spatially restricted gene expression at the neuromuscular junction.