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J. Cell Biol.,
Volume 141, Number 3, May 4, 1998 715-726
* Department of Physiology, University of Basel, Vesalgasse 1, CH-4051 Basel, Switzerland; The neural isoforms of agrin can stimulate
transcription of the acetylcholine receptor (AChR) Department of Research, Stiftung
Tumorbank Basel, University Women's Clinic, CH-4031 Basel, Switzerland; and § Department of Pharmacology, Biozentrum,
University of Basel, CH-4056 Basel, Switzerland
subunit gene in electrically active muscle fibers, as does
the motor neuron upon the formation of a neuromuscular junction. It is not clear, however, whether this induction 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 subunit gene transcription is inhibited in cultured myotubes overexpressing an inactive mutant of the ErbB2 receptor, demonstrating 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 required for their immobilization at heparan sulfate proteoglycans (HSPGs) of the extracellular matrix. In extrasynaptic regions of innervated muscle fibers in vivo,
ectopically expressed neural agrin induces the colocalized accumulation of AChRs, muscle-derived NRGs,
and HSPGs. By using overlay and radioligand-binding
assays we show that the Ig domain of NRGs bind to the
HSPGs agrin and perlecan. These findings show that
neural agrin can induce AChR subunit gene transcription by aggregating muscle HSPGs on the muscle fiber
surface that then serve as a local sink for focal binding
of muscle-derived NRGs to regulate AChR gene expression at the neuromuscular junction.
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