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© The Rockefeller University Press, 0021-9525/1997//671 $5.00
The Journal of Cell Biology, Volume 137, Number 3, , 1997 671-683

Article

Agrin Binds to the Nerve–Muscle Basal Lamina via Laminin



Alain J. Denzer*, Ralph Brandenberger{ddagger}, Matthias Gesemann*, Matthias Chiquet{ddagger}, and Markus A. Ruegg*

* Department of Pharmacology, {ddagger} Department of Biophysical Chemistry, Biozentrum, University of Basel, CH-4056 Basel, Switzerland

Agrin is a heparan sulfate proteoglycan that is required for the formation and maintenance of neuromuscular junctions. During development, agrin is secreted from motor neurons to trigger the local aggregation of acetylcholine receptors (AChRs) and other proteins in the muscle fiber, which together compose the postsynaptic apparatus. After release from the motor neuron, agrin binds to the developing muscle basal lamina and remains associated with the synaptic portion throughout adulthood. We have recently shown that full-length chick agrin binds to a basement membrane-like preparation called MatrigelTM. The first 130 amino acids from the NH2 terminus are necessary for the binding, and they are the reason why, on cultured chick myotubes, AChR clusters induced by full-length agrin are small. In the current report we show that an NH2-terminal fragment of agrin containing these 130 amino acids is sufficient to bind to MatrigelTM and that the binding to this preparation is mediated by laminin-1. The fragment also binds to laminin-2 and -4, the predominant laminin isoforms of the muscle fiber basal lamina. On cultured myotubes, it colocalizes with laminin and is enriched in AChR aggregates. In addition, we show that the effect of full-length agrin on the size of AChR clusters is reversed in the presence of the NH2-terminal agrin fragment. These data strongly suggest that binding of agrin to laminin provides the basis of its localization to synaptic basal lamina and other basement membranes.

Abbreviations used in this paper: AChE, acetylcholinesterase; AChR, acetylcholine receptor; ECM, extracellular marix; HS-GAG, heparan sulfate glycosaminoglycan; HSPG, heparan sulfate proteoglycan; NMJ, neuromuscular junction; NtA, NH2-terminal domain in agrin; VF, vitreous fluid.

Address all correspondence to Markus A. Ruegg, Department of Pharmacology, Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Tel.: 41 61 267 2246 or 2213. Fax: 41 61 267 2208. E-mail: rueegg{at}ubaclu.unibas.ch

Ralph Brandenberger's current address is the Department of Physiology, University of California San Francisco School of Medicine, San Francisco, CA 94143-0724.

Matthias Chiquet's current address is Maurice E. Müller-Institute for Biomechanics, P.O. Box 30, CH-3010 Bern, Switzerland.


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