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 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 beta 1 (rHRG beta 1), the human homolog of ARIA, induces expression of the AChR epsilon gene, the subunit most sensitive to synaptic input. The inducing property of rHRG beta 1 is demonstrated most dramatically in primary muscle cultures from transgenic mice bearing an epsilon 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 bp epsilon 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.
Chu
G C
GC
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Moscoso
L M
LM
Sliwkowski
M X
MX
Merlie
J P
JP
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008813:Mice, Inbred ICR; D008959:Models, Neurological; D009046:Motor Neurons / Q000502:physiology*; D018482:Muscle, Skeletal / Q000294:innervation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020890:Neuregulin-1; D020880:Neuregulins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D013569:Synapses / Q000502:physiology*; D014162:Transfection; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis
D006023:Glycoproteins; D046911:Macromolecular Substances; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D020880:Neuregulins; C490581:Nrg1 protein, mouse; C490580:Nrg1 protein, rat; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D001616:beta-Galactosidase