Agrin Can Mediate Acetylcholine Receptor Gene Expression

The neural isoforms of agrin can stimulate transcription of the acetylcholine receptor (AChR) e subunit gene in electrically active muscle fibers, as does the motor neuron upon the formation of a neuromuscu-lar junction. It is not clear, however, whether this induc-tion involves neuregulins (NRGs), which stimulate AChR subunit gene transcription in vitro by activating ErbB receptors. In this study, we show that agrin-induced induction of AChR e subunit gene transcrip-tion is inhibited in cultured myotubes overexpressing an inactive mutant of the ErbB2 receptor, demonstrat-ing involvement of the NRG/ErbB pathway in agrin-induced AChR expression. Furthermore, salt extracts from the surface of cultured myotubes induce tyrosine phosphorylation of ErbB2 receptors, indicating that muscle cells express biological NRG-like activity on their surface. We further demonstrate by RT-PCR analysis that muscle NRGs have Ig-like domains re-quired for their immobilization at heparan sulfate pro-teoglycans (HSPGs) of the extracellular matrix. In ex-trasynaptic regions of innervated muscle fibers in viv