Abstract
TWO different signalling pathways mediate the localization of acetylcholine receptors (AChRs) to synaptic sites in skeletal muscle. The signal for one pathway is agrin, a protein that triggers a redistribution of previously unlocalized cell surface AChRs to synaptic sites1. The signal for the other pathway is not known, but this signal stimulates transcription of AChR genes in myofibre nuclei near the synaptic site2. Neuregulins, identified originally as a potential ligand for erbB2 (Neu differentiation factor, NDF) 3, stimulate proliferation of Schwann cells (glial growth factor, GGF) 4, increase the rate of AChR synthesis in cultured muscle cells (AChR-inducing activity) 5 and are expressed in motor neurons4,5. These results raise the possibility that neuregulin is the signal that activates AChR genes in synaptic nuclei. Here we show that neuregulin activates AChR gene expression in C2 muscle cells and that the neuregulin response element in the AChR δ-subunit gene is contained in the same 181 base pairs that confer synapse-specific expression in transgenic mice. We use antibodies to show that neuregulins are concentrated at synaptic sites and that, like the extracellular signal that stimulates synapse-specific expression, neuregulins remain at synaptic sites in the absence of nerve and muscle. We show that C2 muscle cells contain erbB2 and erbB3 messenger RNA but little or no erbB4 mRNA, and that neuregulin stimulates tyrosine phosphorylation of erbB2 and erbB3, indicating that neuregulin signalling in skeletal muscle may be mediated by a complex of erbB2 and erbB3.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
McMahan, U. J. Cold Spring Harb. Symp. quant. Biol. 55, 407–418 (1990).
Burden, S. J. Trends Genet. 9, 12–16 (1993).
Wen, D. et al. Cell 69, 559–572 (1992).
Marchionni, M. A. et al. Nature 362, 312–318 (1993).
Falls, D. L. et al. Cell 72, 801–815 (1993).
Simon, A. M., Hoppe, P. & Burden, S. J. Development 114, 545–553 (1992).
Klarsfeld, A. et al. EMBO J. 10, 625–632 (1991).
Sanes, J. R. et al. Development 113, 1181–1191 (1991).
Tang, J., Jo, S. A. & Burden, S. J. Development 120, 1799–1804 (1994).
Mudge, A. W. Curr. Blol. 3, 361–364 (1993).
Holmes, W. E. et al. Science 256, 1205–1210 (1992).
Gundersen, K., Sanes, J. R. & Merlie, J. P. J. Cell Blol. 123, 1535–1544 (1993).
Jo, S. A. & Burden, S. J. Development 115, 673–680 (1992).
Brenner, H. R., Herczeg, A. & Slater, C. R. Development 116, 41–53 (1992).
Goldman, D., Carlson, B. M. & Staple, J. Neuron 7, 649–658 (1991).
Carraway, K. L. et al. J. biol. Chem. 269, 14303–14306 (1994).
Plowman, G. D. et al. Nature 366, 473–475 (1993).
Plowman, G. D. et al. Proc. natn. Acad. Sci. U.S.A. 90, 1746–1750 (1993).
Kraus, M. H., Issing, W., Miki, T., Popescu, N. C. & Aaronson, S. A. Proc. natn. Acad. Sci. U.S.A. 86, 9193–9197 (1989).
Lai, C. & Lemke, G. Neuron 6, 691–704 (1991).
Carraway, K. L. & Cantley, L. C. Cell 78, 5–8 (1994).
Simon, A. M. & Burden, S. J. Mol. cell. Biol. 13, 5133–5140 (1993).
Shah, N. M., Marchionni, M. A., Isaacs, I., Stroobant, P. & Anderson, D. J. Cell 77, 349–360 (1994).
Martinou, J.-C., Falls, D. L., Fischbach, G. D. & Merlie, J. P. Proc. natn. Acad. Sci. U.S.A. 88, 7669–7673 (1991).
Buckley, K. M. & Kelly, R. B. J. Cell Biol. 100, 1284–1294 (1985).
Sanes, J. R. & Chiu, A. Y. Cold Spring Harb. Symp. quant. Biol. 48, 667–678 (1983).
Bargmann, C. I., Hung, M. C. & Weinberg, R. A. Nature 319, 226–230 (1986).
Plowman, G. D. et al. Proc. natn. Acad. Sci. U.S.A. 87, 4905–4909 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ahn Jo, S., Zhu, X., Marchionni, M. et al. Neuregulins are concentrated at nerve-muscle synapses and activate ACh–receptor gene expression. Nature 373, 158–161 (1995). https://doi.org/10.1038/373158a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/373158a0
This article is cited by
-
Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation
Scientific Reports (2018)
-
Neuregulin-1β modulates myogenesis in septic mouse serum-treated C2C12 myotubes in vitro through PPARγ/NF-κB signaling
Molecular Biology Reports (2018)
-
Functional analysis of human intrafusal fiber innervation by human γ-motoneurons
Scientific Reports (2017)
-
Neuromuscular synaptogenesis: coordinating partners with multiple functions
Nature Reviews Neuroscience (2014)
-
Increased expression of neuregulin-1 in differentiating muscle satellite cells and in motoneurons during muscle regeneration
Acta Neuropathologica (2007)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.