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© The Rockefeller University Press, 0021-9525/1997//1507 $5.00
The Journal of Cell Biology, Volume 139, Number 6, , 1997 1507-1521

Article

Distribution and Function of Laminins in the Neuromuscular System of Developing, Adult, and Mutant Mice



Bruce L. Patton*, Jeffrey H. Miner*,{ddagger}, Arlene Y. Chiu§, and Joshua R. Sanes*

* Department of Anatomy and Neurobiology, {ddagger} Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110; and § Division of Neuroscience, Beckman Research Institute of the City of Hope, Duarte, California 91010

Laminins, heterotrimers of {alpha}, β, and {gamma} chains, are prominent constituents of basal laminae (BLs) throughout the body. Previous studies have shown that laminins affect both myogenesis and synaptogenesis in skeletal muscle. Here we have studied the distribution of the 10 known laminin chains in muscle and peripheral nerve, and assayed the ability of several heterotrimers to affect the outgrowth of motor axons. We show that cultured muscle cells express four different {alpha} chains ({alpha}1, {alpha}2, {alpha}4, and {alpha}5), and that developing muscles incorporate all four into BLs. The portion of the muscle's BL that occupies the synaptic cleft contains at least three {alpha} chains and two β chains, but each is regulated differently. Initially, the {alpha}2, {alpha}4, {alpha}5, and β1 chains are present both extrasynaptically and synaptically, whereas β2 is restricted to synaptic BL from its first appearance. As development proceeds, {alpha}2 remains broadly distributed, whereas {alpha}4 and {alpha}5 are lost from extrasynaptic BL and β1 from synaptic BL. In adults, {alpha}4 is restricted to primary synaptic clefts whereas {alpha}5 is present in both primary and secondary clefts. Thus, adult extrasynaptic BL is rich in laminin 2 ({alpha}2β1{gamma}1), and synaptic BL contains laminins 4 ({alpha}2β2{gamma}1), 9 ({alpha}4β2{gamma}1), and 11 ({alpha}5β2{gamma}1). Likewise, in cultured muscle cells, {alpha}2 and β1 are broadly distributed but {alpha}5 and β2 are concentrated at acetylcholine receptor–rich "hot spots," even in the absence of nerves. The endoneurial and perineurial BLs of peripheral nerve also contain distinct laminin chains: {alpha}2, β1, {gamma}1, and {alpha}4, {alpha}5, β2, {gamma}1, respectively. Mutation of the laminin {alpha}2 or β2 genes in mice not only leads to loss of the respective chains in both nerve and muscle, but also to coordinate loss and compensatory upregulation of other chains. Notably, loss of β2 from synaptic BL in β2–/– "knockout" mice is accompanied by loss of {alpha}5, and decreased levels of {alpha}2 in dystrophic {alpha}2dy/dy mice are accompanied by compensatory retention of {alpha}4. Finally, we show that motor axons respond in distinct ways to different laminin heterotrimers: they grow freely between laminin 1 ({alpha}1β1{gamma}1) and laminin 2, fail to cross from laminin 4 to laminin 1, and stop upon contacting laminin 11. The ability of laminin 11 to serve as a stop signal for growing axons explains, in part, axonal behaviors observed at developing and regenerating synapses in vivo.

Abbreviations used in this paper: AChR, acetylcholine receptors; BL, basal lamina; E, embryonic day.

Address all correspondence to Joshua R. Sanes, Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Fax: (314) 747-1150. E-mail: sanesj{at}thalamus.wustl.edu


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