Development of the Vertebrate Neuromuscular Junction

  • Michael A. FoxEmail author


The precise alignment of nerve terminals to postsynaptic specializations suggests that trans-synaptic cues direct synapse formation. As with much of our understanding of synaptic function, initial insight into both the presence and the identity of these synaptogenic cues was derived from studies at the vertebrate neuromuscular junction (NMJ), a synapse formed between motoneurons and skeletal muscle fibers. Unlike central synapses, the wide synaptic cleft of the NMJ contains a network of cell-associated extracellular glycoproteins in the form of a specialized basal lamina (BL). The discovery that components of this synaptic BL direct pre- and postsynaptic differentiation has fueled three decades of intense research on the molecular signals regulating NMJ formation. Here, in addition to describing the organization and morphological development of the vertebrate NMJ, the roles of these extracellular adhesion molecules in the formation, maturation, and maintenance of this synapse are discussed.


Synapse formation Basal lamina Laminin Agrin Collagen IV Nidogen 


  1. Ackley, B. D., Kang, S. H., Crew, J. R., Suh, C., Jin, Y., and Kramer, J. M. (2003). The basement membrane components Nidogen and type XVIII collagen regulate organization of neuromuscular junctions in Caenorhabditis elegans. J Neurosci 23, 3577–3587PubMedGoogle Scholar
  2. Ackley, B. D., Harrington, R. J., Hudson, M. L., Williams, L., Kenyon, C. J., Chisholm, A. D., and Jin, Y. (2005). The two isoforms of the Caenorhabditis elegans leukocyte-common antigen related receptor tyrosine phosphatase PTP-3 function independently in axon guidance and synapse formation. J Neurosci 25, 7517–7528PubMedCrossRefGoogle Scholar
  3. Adams, J. C. (2002). Molecular organisation of cell-matrix contacts: essential multiprotein assemblies in cell and tissue function. Expert Rev Mol Med 4, 1–24CrossRefGoogle Scholar
  4. Akaaboune, M., Grady, R. M., Turney, S., Sanes, J. R., and Lichtman, J. W. (2002). Neurotransmitter receptor dynamics studied in vivo by reversible photo-unbinding of fluorescent ligands. Neuron 34, 865–876PubMedCrossRefGoogle Scholar
  5. Anderson, M. J., and Cohen, M. W. (1977). Nerve-induced and spontaneous redistribution of acetylcholine receptors on cultured muscle cells. J Physiol 268, 757–773PubMedGoogle Scholar
  6. Andonian, M. H., and Fahim, M. A. (1989). Nerve terminal morphology in C57BL/6NNia mice at different ages. J Gerontol 44, B43–51PubMedGoogle Scholar
  7. Auld, D. S., Colomar, A., Belair, E. L., Castonguay, A., Pinard, A., Rousse, I., Thomas, S., and Robitaille, R. (2003). Modulation of neurotransmission by reciprocal synapse-glial interactions at the neuromuscular junction. J Neurocytol 32, 1003–1015PubMedCrossRefGoogle Scholar
  8. Balice-Gordon, R. J., and Lichtman, J. W. (1993). In vivo observations of pre- and postsynaptic changes during the transition from multiple to single innervation at developing neuromuscular junctions. J Neurosci 13, 834–855PubMedGoogle Scholar
  9. Banker, B. Q., Hirst, N. S., Chester, C. S., and Fok, R. Y. (1979). Histometric and electron cytochemical study of muscle in the dystrophic mouse. Ann N Y Acad Sci 317, 115–131PubMedGoogle Scholar
  10. Banks, G. B., Fuhrer, C., Adams, M. E., and Froehner, S. C. (2003) The postsynaptic submembrane machinery at the neuromuscular junction: requirement for rapsyn and the utrophin/dystrophin-associated complex. J Neurocytol 32, 709–726PubMedCrossRefGoogle Scholar
  11. Berg, D. K., Kelly, R. B., Sargent, P. B., Williamson, P., and Hall, Z. W. (1972). Binding of bungarotoxin to acetylcholine receptors in mammalian muscle (snake venom-denervated muscle-neonatal muscle-rat diaphragm-SDS-polyacrylamide gel electrophoresis). Proc Natl Acad Sci U S A 69, 147–151PubMedCrossRefGoogle Scholar
  12. Bernard, C. (1856). Analyse physiologique des propriétés des systèmes musculaires et nerveux au moyen du curare. CR Acad Sci, 825–829Google Scholar
  13. Berrier, A. L., and Yamada, K. M. (2007). Cell-matrix adhesion. J Cell Physiol 213, 565–573PubMedCrossRefGoogle Scholar
  14. Bevan, S., and Steinbach, J. H. (1977). The distribution of alpha-bungarotoxin binding sites of mammalian skeletal muscle developing in vivo. J Physiol 267, 195–213PubMedGoogle Scholar
  15. Birks, R., Huxley, H. E., and Katz, B. (1960). The fine structure of the neuromuscular junction of the frog. J Physiol 150, 134–144PubMedGoogle Scholar
  16. Bixby, J. L. (1995). Collagen synthesis inhibition reduces clustering of heparan sulfate proteoglycan and acetylcholine receptors but not agrin or p65, at neuromuscular contacts in vitro. J Neurobiol 26, 262–272PubMedCrossRefGoogle Scholar
  17. Bowe, M. A., and Fallon, J. R. (1995). The role of agrin in synapse formation. Annu Rev Neurosci 18, 443–462PubMedCrossRefGoogle Scholar
  18. Brown, G. L., Dale, H. H., and Feldberg, W. (1936). Reactions of the normal mammalian muscle to acetylcholine and to eserine. J Physiol 87, 394–424PubMedGoogle Scholar
  19. Buchanan, J., Sun, Y. A., and Poo, M. M. (1989). Studies of nerve-muscle interactions in Xenopus cell culture: fine structure of early functional contacts. J Neurosci 9, 1540–1554PubMedGoogle Scholar
  20. Burden, S. J., Sargent, P. B., and McMahan, U. J. (1979). Acetylcholine receptors in regenerating muscle accumulate at original synaptic sites in the absence of the nerve. J Cell Biol 82, 412–425PubMedCrossRefGoogle Scholar
  21. Burden, S. J., DePalma, R. L., and Gottesman, G. S. (1983). Crosslinking of proteins in acetylcholine receptor-rich membranes: association between the beta-subunit and the 43 kd subsynaptic protein. Cell 35, 687–692PubMedCrossRefGoogle Scholar
  22. Burgess, R. W., Nguyen, Q. T., Son, Y. J., Lichtman, J. W., and Sanes, J. R. (1999). Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction. Neuron 23, 33–44PubMedCrossRefGoogle Scholar
  23. Cajal, S.R.Y. (1928). Degeneration and Regeneration of the Nervous System. (London, Oxford University Press)Google Scholar
  24. Campanelli, J. T., Roberds, S. L., Campbell, K. P., and Scheller, R. H. (1994). A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering. Cell 77, 663–674PubMedCrossRefGoogle Scholar
  25. Carr, C., Fischbach, G. D., and Cohen, J. B. (1989). A novel 87,000-Mr protein associated with acetylcholine receptors in Torpedo electric organ and vertebrate skeletal muscle. J Cell Biol 109, 1753–1764PubMedCrossRefGoogle Scholar
  26. Cartaud, J., Cartaud, A., Kordeli, E., Ludosky, M. A., Marchand, S., and Stetzkowski-Marden, F. (2000). The torpedo electrocyte: a model system to study membrane-cytoskeleton interactions at the postsynaptic membrane. Microsc Res Tech 49, 73–83PubMedCrossRefGoogle Scholar
  27. Cartaud, A., Strochlic, L., Guerra, M., Blanchard, B., Lambergeon, M., Krejci, E., Cartaud, J., and Legay, C. (2004). MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J Cell Biol 165, 505–515PubMedCrossRefGoogle Scholar
  28. Chang, C. C., and Lee, C. Y. (1963). Isolation of neurotoxins from the venom of bungarus multicinctus and their modes of neuromuscular blocking action. Arch Int Pharmacodyn Ther 144, 241–257PubMedGoogle Scholar
  29. Changeux, J. P., Meunier, J. C., and Huchet, M. (1971). Studies on the cholinergic receptor protein of Electrophorus electricus. I. An assay in vitro for the cholinergic receptor site and solubilization of the receptor protein from electric tissue. Mol Pharmacol 7, 538–553PubMedGoogle Scholar
  30. Chiu, A. Y., and Ko, J. (1994). A novel epitope of entactin is present at the mammalian neuromuscular junction. J Neurosci 14, 2809–2817PubMedGoogle Scholar
  31. Christopherson, K. S., Ullian, E. M., Stokes, C. C., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., and Barres, B. A. (2005). Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433PubMedCrossRefGoogle Scholar
  32. Cohen, M. W., and Godfrey, E. W. (1992). Early appearance of and neuronal contribution to agrin-like molecules at embryonic frog nerve-muscle synapses formed in culture. J Neurosci 12, 2982–2992PubMedGoogle Scholar
  33. Cohen, M. W., Hoffstrom, B. G., and DeSimone, D. W. (2000). Active zones on motor nerve terminals contain alpha 3beta 1 integrin. J Neurosci 20, 4912–4921PubMedGoogle Scholar
  34. Colognato, H., and Yurchenco, P. D. (2000). Form and function: the laminin family of heterotrimers. Dev Dyn 218, 213–234PubMedCrossRefGoogle Scholar
  35. Colomar, A., and Robitaille, R. (2004). Glial modulation of synaptic transmission at the neuromuscular junction. Glia 47, 284–289PubMedCrossRefGoogle Scholar
  36. Connold, A. L., Evers, J. V., and Vrbova, G. (1986). Effect of low calcium and protease inhibitors on synapse elimination during postnatal development in the rat soleus muscle. Brain Res 393, 99–107PubMedGoogle Scholar
  37. Cote, P. D., Moukhles, H., Lindenbaum, M., and Carbonetto, S. (1999). Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses. Nat Genet 23, 338–342PubMedCrossRefGoogle Scholar
  38. Couteaux, R. (1944). Nouvelles observations sur la structure de la plaque motrice et interprétation des rapports myo-neuraux. CR Soc Biol 138, 976–979Google Scholar
  39. Couteaux, R. (1946). Sur les gouttières synaptiques du muscle strié. CR Soc Biol 140, 270–273Google Scholar
  40. Couteaux, R., and Pecot-Dechavassine, M. (1970). Synaptic vesicles and pouches at the level of “active zones” of the neuromuscular junction. C R Acad Sci Hebd Seances Acad Sci D 271, 2346–2349PubMedGoogle Scholar
  41. Covault, J., and Sanes, J. R. (1985). Neural cell adhesion molecule (N-CAM) accumulates in denervated and paralyzed skeletal muscles. Proc Natl Acad Sci U S A 82, 4544–4548PubMedCrossRefGoogle Scholar
  42. Covault, J., and Sanes, J. R. (1986). Distribution of N-CAM in synaptic and extrasynaptic portions of developing and adult skeletal muscle. J Cell Biol 102, 716–730PubMedCrossRefGoogle Scholar
  43. Dai, Z., and Peng, H. B. (1995). Presynaptic differentiation induced in cultured neurons by local application of basic fibroblast growth factor. J Neurosci 15, 5466–5475PubMedGoogle Scholar
  44. Dale, H. H., Feldberg, W., and Vogt, M. (1936). Release of acetylcholine at voluntary motor nerve endings. J Physiol 86, 353–380PubMedGoogle Scholar
  45. DeChiara, T. M., Bowen, D. C., Valenzuela, D. M., Simmons, M. V., Poueymirou, W. T., Thomas, S., Kinetz, E., Compton, D. L., Rojas, E., Park, J. S., et al. (1996). The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85, 501–512PubMedCrossRefGoogle Scholar
  46. del Castillo, J., and Katz, B. (1956). Localization of active spots within the neuromuscular junction of the frog. J Physiol 132, 630–649PubMedGoogle Scholar
  47. Demestre, M., Orth, M., Wells, G. M., Gearing, A. J., Hughes, R. A., and Gregson, N. A. (2005). Characterization of matrix metalloproteinases in denervated muscle. Neuropathol Appl Neurobiol 31, 545–555PubMedCrossRefGoogle Scholar
  48. Dimitropoulou, A., and Bixby, J. L. (2005). Motor neurite outgrowth is selectively inhibited by cell surface MuSK and agrin. Mol Cell Neurosci 28, 292–302PubMedCrossRefGoogle Scholar
  49. Douville, P. J., Harvey, W. J., and Carbonetto, S. (1988). Isolation and partial characterization of high affinity laminin receptors in neural cells. J Biol Chem 263, 14964–14969PubMedGoogle Scholar
  50. Duclert, A., and Changeux, J. P. (1995). Acetylcholine receptor gene expression at the developing neuromuscular junction. Physiol Rev 75, 339–368PubMedGoogle Scholar
  51. Edmonds, B., Gibb, A. J., and Colquhoun, D. (1995a). Mechanisms of activation of glutamate receptors and the time course of excitatory synaptic currents. Annu Rev Physiol 57, 495–519PubMedCrossRefGoogle Scholar
  52. Edmonds, B., Gibb, A. J., and Colquhoun, D. (1995b). Mechanisms of activation of muscle nicotinic acetylcholine receptors and the time course of endplate currents. Annu Rev Physiol 57, 469–493PubMedCrossRefGoogle Scholar
  53. Egles, C., Claudepierre, T., Manglapus, M. K., Champliaud, M. F., Brunken, W. J., and Hunter, D. D. (2007). Laminins containing the beta2 chain modulate the precise organization of CNS synapses. Mol Cell Neurosci 34, 288–298PubMedCrossRefGoogle Scholar
  54. English, A. W.( 2003). Cytokines, growth factors and sprouting at the neuromuscular junction. J Neurocytol 32, 943–960PubMedCrossRefGoogle Scholar
  55. Ervasti, J. M., and Campbell, K. P. (1991). Membrane organization of the dystrophin-glycoprotein complex. Cell 66, 1121–1131PubMedCrossRefGoogle Scholar
  56. Escher, P., Lacazette, E., Courtet, M., Blindenbacher, A., Landmann, L., Bezakova, G., Lloyd, K. C., Mueller, U., and Brenner, H. R. (2005). Synapses form in skeletal muscles lacking neuregulin receptors. Science 308, 1920–1923PubMedCrossRefGoogle Scholar
  57. Fallon, J. R., Nitkin, R. M., Reist, N. E., Wallace, B. G., and McMahan, U. J. (1985). Acetylcholine receptor-aggregating factor is similar to molecules concentrated at neuromuscular junctions. Nature 315, 571–574PubMedCrossRefGoogle Scholar
  58. Fallon, J. R., and Gelfman, C. E. (1989). Agrin-related molecules are concentrated at acetylcholine receptor clusters in normal and aneural developing muscle. J Cell Biol 108, 1527–1535PubMedCrossRefGoogle Scholar
  59. Fallon, J. R., and Hall, Z. W. (1994). Building synapses: agrin and dystroglycan stick together. Trends Neurosci 17, 469–473PubMedCrossRefGoogle Scholar
  60. Falls, D. L., Rosen, K. M., Corfas, G., Lane, W. S., and Fischbach, G. D. (1993). ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72, 801–815PubMedCrossRefGoogle Scholar
  61. Falls, D. L. (2003). Neuregulins and the neuromuscular system: 10 years of answers and questions. J Neurocytol 32, 619–647PubMedCrossRefGoogle Scholar
  62. Fatt, P., and Katz, B. (1950). Some observations on biological noise. Nature 166, 597–598PubMedCrossRefGoogle Scholar
  63. Fatt, P., and Katz, B. (1952). Spontaneous subthreshold activity at motor nerve endings. J Physiol 117, 109–128PubMedGoogle Scholar
  64. Feng, G., Krejci, E., Molgo, J., Cunningham, J. M., Massoulie, J., and Sanes, J. R. (1999). Genetic analysis of collagen Q: roles in acetylcholinesterase and butyrylcholinesterase assembly and in synaptic structure and function. J Cell Biol 144, 1349–1360PubMedCrossRefGoogle Scholar
  65. Feng, Z., Koirala, S., and Ko, C. P. (2005). Synapse-glia interactions at the vertebrate neuromuscular junction. Neuroscientist 11, 503–513PubMedCrossRefGoogle Scholar
  66. Ferns, M. J., Campanelli, J. T., Hoch, W., Scheller, R. H., and Hall, Z. (1993). The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. Neuron 11, 491–502PubMedCrossRefGoogle Scholar
  67. Ferns, M., and Carbonetto, S. (2001). Challenging the neurocentric view of neuromuscular synapse formation. Neuron 30, 311–314PubMedCrossRefGoogle Scholar
  68. Fertuck, H. C., and Salpeter, M. M. (1974). Localization of acetylcholine receptor by 125I-labeled alpha-bungarotoxin binding at mouse motor endplates. Proc Natl Acad Sci U S A 71, 1376–1378PubMedCrossRefGoogle Scholar
  69. Fertuck, H. C., and Salpeter, M. M. (1976). Quantitation of junctional and extrajunctional acetylcholine receptors by electron microscope autoradiography after 125I-alpha-bungarotoxin binding at mouse neuromuscular junctions. J Cell Biol 69, 144–158PubMedCrossRefGoogle Scholar
  70. Flanagan-Steet, H., Fox, M. A., Meyer, D., and Sanes, J. R. (2005). Neuromuscular synapses can form in vivo by incorporation of initially aneural postsynaptic specializations. Development 132, 4471–4481PubMedCrossRefGoogle Scholar
  71. Flucher, B. E., and Daniels, M. P. (1989). Distribution of Na+ channels and ankyrin in neuromuscular junctions is complementary to that of acetylcholine receptors and the 43 kd protein. Neuron 3, 163–175PubMedCrossRefGoogle Scholar
  72. Fontaine, B., Klarsfeld, A., Hokfelt, T., and Changeux, J. P. (1986). Calcitonin gene-related peptide, a peptide present in spinal cord motoneurons, increases the number of acetylcholine receptors in primary cultures of chick embryo myotubes. Neurosci Lett 71, 59–65PubMedCrossRefGoogle Scholar
  73. Fox, M. A., and Umemori, H. (2006). Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J Neurochem 97, 1215–1231.Google Scholar
  74. Fox, M. A., Latvanlehto, A., Pihlajaniemi, T., and Sanes, J. R. (2006). Collagen XIII is critical for postsynaptic differentiation and maturation at the NMJ. Paper presented at: Society for Neuroscience. (Atlanta, GA.)Google Scholar
  75. Fox, M. A., Sanes, J. R., Borza, D. B., Eswarakumar, V. P., Fassler, R., Hudson, B. G., John, S. W., Ninomiya, Y., Pedchenko, V., Pfaff, S. L., et al. (2007a). Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell 129, 179–193PubMedCrossRefGoogle Scholar
  76. Fox, M. A., Smyth, N., and Sanes, J. R. (2007b). Nidogen at the neuromuscular junction. Paper presented at: Society for Neuroscience. (San Diego, CA)Google Scholar
  77. Frank, E., and Fischbach, G. D. (1979). Early events in neuromuscular junction formation in vitro: induction of acetylcholine receptor clusters in the postsynaptic membrane and morphology of newly formed synapses. J Cell Biol 83, 143–158PubMedCrossRefGoogle Scholar
  78. Gautam, M., Noakes, P. G., Moscoso, L., Rupp, F., Scheller, R. H., Merlie, J. P., and Sanes, J. R. (1996). Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85, 525–535PubMedCrossRefGoogle Scholar
  79. Gawlak, M., Go´rkiewicz, T., Gorlewicz, A., Konopacki, F. A., Kaczmarek, L., and Wilczynski, G. M. (2009). High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses. Neuroscience 158(1), 167-176Google Scholar
  80. Gee, S. H., Montanaro, F., Lindenbaum, M. H., and Carbonetto, S. (1994). Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell 77, 675–686PubMedCrossRefGoogle Scholar
  81. Gilbert, J. J., Steinberg, M. C., and Banker, B. Q. (1973). Ultrastructural alterations of the motor end plate in myotonic dystrophy of the mouse (dy2J dy2J). J Neuropathol Exp Neurol 32, 345–364PubMedCrossRefGoogle Scholar
  82. Glass, D. J., DeChiara, T. M., Stitt, T. N., DiStefano, P. S., Valenzuela, D. M., and Yancopoulos, G. D. (1996). The receptor tyrosine kinase MuSK is required for neuromuscular junction formation and is a functional receptor for agrin. Cold Spring Harb Symp Quant Biol 61, 435–444PubMedGoogle Scholar
  83. Glass, D. J., Apel, E. D., Shah, S., Bowen, D. C., DeChiara, T. M., Stitt, T. N., Sanes, J. R., and Yancopoulos, G. D. (1997). Kinase domain of the muscle-specific receptor tyrosine kinase (MuSK) is sufficient for phosphorylation but not clustering of acetylcholine receptors: required role for the MuSK ectodomain? Proc Natl Acad Sci U S A 94, 8848–8853PubMedCrossRefGoogle Scholar
  84. Glicksman, M. A., and Sanes, J. R. (1983). Differentiation of motor nerve terminals formed in the absence of muscle fibres. J Neurocytol 12, 661–671PubMedCrossRefGoogle Scholar
  85. Godfrey, E. W., Nitkin, R. M., Wallace, B. G., Rubin, L. L., and McMahan, U. J. (1984). Components of Torpedo electric organ and muscle that cause aggregation of acetylcholine receptors on cultured muscle cells. J Cell Biol 99, 615–627PubMedCrossRefGoogle Scholar
  86. Goridis, C., and Brunet, J. F. (1992). NCAM: structural diversity, function and regulation of expression. Semin Cell Biol 3, 189–197PubMedGoogle Scholar
  87. Gould, D. B., Phalan, F. C., Breedveld, G. J., van Mil, S. E., Smith, R. S., Schimenti, J. C., Aguglia, U., van der Knaap, M. S., Heutink, P., and John, S. W. (2005). Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308, 1167–1171PubMedCrossRefGoogle Scholar
  88. Green, T. L., Hunter, D. D., Chan, W., Merlie, J. P., and Sanes, J. R. (1992). Synthesis and assembly of the synaptic cleft protein S-laminin by cultured cells. J Biol Chem 267, 2014–2022PubMedGoogle Scholar
  89. Heino, J. (2007). The collagen family members as cell adhesion proteins. Bioessays 29, 1001–1010PubMedCrossRefGoogle Scholar
  90. Ho, M. S., Bose, K., Mokkapati, S., Nischt, R., and Smyth, N. (2008). Nidogens-Extracellular matrix linker molecules. Microsc Res Tech 71, 387–395PubMedCrossRefGoogle Scholar
  91. Hoch, W., Ferns, M., Campanelli, J. T., Hall, Z. W., and Scheller, R. H. (1993). Developmental regulation of highly active alternatively spliced forms of agrin. Neuron 11, 479–490PubMedCrossRefGoogle Scholar
  92. Hodges, S. H., Anderson, A. L., and Connor, N. P. (2004). Remodeling of neuromuscular junctions in aged rat genioglossus muscle. Ann Otol Rhinol Laryngol 113, 175–179PubMedGoogle Scholar
  93. Hudson, B. G., Tryggvason, K., Sundaramoorthy, M., and Neilson, E. G. (2003). Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 348, 2543–2556PubMedCrossRefGoogle Scholar
  94. Hunter, D. D., Shah, V., Merlie, J. P., and Sanes, J. R. (1989). A laminin-like adhesive protein concentrated in the synaptic cleft of the neuromuscular junction. Nature 338, 229–234PubMedCrossRefGoogle Scholar
  95. Hunter, D. D., Cashman, N., Morris-Valero, R., Bulock, J. W., Adams, S. P., and Sanes, J. R. (1991). An LRE (leucine-arginine-glutamate)-dependent mechanism for adhesion of neurons to S-laminin. J Neurosci 11, 3960–3971PubMedGoogle Scholar
  96. Hynes, R. O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687PubMedCrossRefGoogle Scholar
  97. Ibraghimov-Beskrovnaya, O., Ervasti, J. M., Leveille, C. J., Slaughter, C. A., Sernett, S. W., and Campbell, K. P. (1992). Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355, 696–702PubMedCrossRefGoogle Scholar
  98. Israel, M., Manaranche, R., Mastour-Frachon, P., and Morel, N. (1976). Isolation of pure cholinergic nerve endings from the electric organ of Torpedo marmorata. Biochem J 160, 113–115PubMedGoogle Scholar
  99. Jacobson, C., Cote, P. D., Rossi, S. G., Rotundo, R. L., and Carbonetto, S. (2001). The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. J Cell Biol 152, 435–450PubMedCrossRefGoogle Scholar
  100. Jaworski, A., and Burden, S. J. (2006). Neuromuscular synapse formation in mice lacking motor neuron- and skeletal muscle-derived Neuregulin-1. J Neurosci 26, 655–661PubMedCrossRefGoogle Scholar
  101. Jennings, C. G., Dyer, S. M., and Burden, S. J. (1993). Muscle-specific trk-related receptor with a kringle domain defines a distinct class of receptor tyrosine kinases. Proc Natl Acad Sci U S A 90, 2895–2899PubMedCrossRefGoogle Scholar
  102. Jessell, T. M., Siegel, R. E., and Fischbach, G. D. (1979). Induction of acetylcholine receptors on cultured skeletal muscle by a factor extracted from brain and spinal cord. Proc Natl Acad Sci U S A 76, 5397–5401PubMedCrossRefGoogle Scholar
  103. Jin, Y., and Garner, C. C. (2008). Molecular mechanisms of presynaptic differentiation. Annu Rev Cell Dev Biol 24, 237–262. ReviewGoogle Scholar
  104. Juranek, J., Mukherjee, K., Rickmann, M., Martens, H., Calka, J., Südhof, T. C., and Jahn, R. (2006). Differential expression of active zone proteins in neuromuscular junctions suggests functional diversification. Eur J Neurosci 24, 3043–3052PubMedCrossRefGoogle Scholar
  105. Kadler, K. E., Baldock, C., Bella, J., and Boot-Handford, R. P. (2007). Collagens at a glance. J Cell Sci 120, 1955–1958PubMedCrossRefGoogle Scholar
  106. Kalcheim, C., Duksin, D., and Vogel, Z. (1982a). Involvement of collagen in the aggregation of acetylcholine receptors on cultured muscle cells. J Biol Chem 257, 12722–12727PubMedGoogle Scholar
  107. Kalcheim, C., Duksin, D., and Vogel, Z. (1982b). Aggregation of acetylcholine receptors in nerve-muscle cocultures is decreased by inhibitors of collagen production. Neurosci Lett 31, 265–270PubMedCrossRefGoogle Scholar
  108. Kalluri, R. (2003). Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3, 422–433PubMedCrossRefGoogle Scholar
  109. Kang, H., Tian, L., and Thompson, W. (2003). Terminal Schwann cells guide the reinnervation of muscle after nerve injury. J Neurocytol 32, 975–985PubMedCrossRefGoogle Scholar
  110. Kawashima, S., Imamura, Y., Chandana, E. P., Noda, T., Takahashi, R., Adachi, E., Takahashi, C., and Noda, M. (2008). Localization of the membrane-anchored MMP-regulator RECK at the neuromuscular junctions. J Neurochem 104, 376–385PubMedGoogle Scholar
  111. Keller-Peck, C. R., Walsh, M. K., Gan, W. B., Feng, G., Sanes, J. R., and Lichtman, J. W. (2001). Asynchronous synapse elimination in neonatal motor units: studies using GFP transgenic mice. Neuron 31, 381–394PubMedCrossRefGoogle Scholar
  112. Kherif, S., Dehaupas, M., Lafuma, C., Fardeau, M., and Alameddine, H. S. (1998). Matrix metalloproteinases MMP-2 and MMP-9 in denervated muscle and injured nerve. Neuropathol Appl Neurobiol 24, 309–319PubMedCrossRefGoogle Scholar
  113. Kim, N., and Burden, S. J. (2008). MuSK controls where motor axons grow and form synapses. Nat Neurosci 11, 19–27PubMedCrossRefGoogle Scholar
  114. Knight, D., Tolley, L. K., Kim, D. K., Lavidis, N. A., and Noakes, P. G. (2003). Functional analysis of neurotransmission at beta2-laminin deficient terminals. J Physiol 546, 789–800PubMedCrossRefGoogle Scholar
  115. Koirala, S., Reddy, L. V., and Ko, C. P. (2003). Roles of glial cells in the formation, function, and maintenance of the neuromuscular junction. J Neurocytol 32, 987–1002PubMedCrossRefGoogle Scholar
  116. Ksiazek, I., Burkhardt, C., Lin, S., Seddik, R., Maj, M., Bezakova, G., Jucker, M., Arber, S., Caroni, P., Sanes, J. R., et al. (2007). Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. J Neurosci 27, 7183–7195PubMedCrossRefGoogle Scholar
  117. Kuffler, S. W., and Yoshikami, D. (1975). The number of transmitter molecules in a quantum: an estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J Physiol 251, 465–482PubMedGoogle Scholar
  118. Kummer, T. T., Misgeld, T., Lichtman, J. W., and Sanes, J. R. (2004). Nerve-independent formation of a topologically complex postsynaptic apparatus. J Cell Biol 164, 1077–1087PubMedCrossRefGoogle Scholar
  119. Kummer, T. T., Misgeld, T., and Sanes, J. R. (2006). Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost. Curr Opin Neurobiol 16, 74–82PubMedCrossRefGoogle Scholar
  120. Kühne, W. (1862). Über die peripherischen Endorgane der motorischen Nerven (Leipzig, W. Engelmann)Google Scholar
  121. Kühne, W. (1887). Neue Untersuchungen über motorische Nervenendigungen. Z Biol 23, 1–148Google Scholar
  122. Kühne, W. (1888). On the origin and the causation of vital movement. Proc R Soc Lond B 4, 427–447Google Scholar
  123. Lai, K. O., and Ip, N. Y. (2003). Postsynaptic signaling of new players at the neuromuscular junction. J Neurocytol 32, 727–741PubMedCrossRefGoogle Scholar
  124. Land, B. R., Harris, W. V., Salpeter, E. E., and Salpeter, M. M. (1984). Diffusion and binding constants for acetylcholine derived from the falling phase of miniature endplate currents. Proc Natl Acad Sci U S A 81, 1594–1598PubMedCrossRefGoogle Scholar
  125. Lee, C. Y., Tseng, L. F., and Chiu, T. H. (1967). Influence of denervation on localization of neurotoxins from clapid venoms in rat diaphragm. Nature 215, 1177–1178PubMedCrossRefGoogle Scholar
  126. Libby, R. T., Lavallee, C. R., Balkema, G. W., Brunken, W. J., and Hunter, D. D. (1999). Disruption of laminin beta2 chain production causes alterations in morphology and function in the CNS. J Neurosci 19, 9399–9411PubMedGoogle Scholar
  127. Lin, W., Burgess, R. W., Dominguez, B., Pfaff, S. L., Sanes, J. R., and Lee, K. F. (2001). Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410, 1057–1064PubMedCrossRefGoogle Scholar
  128. Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E. P., Gage, F. H., and Lee, K. F. (2005). Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46, 569–579PubMedCrossRefGoogle Scholar
  129. Lin, S., Landmann, L., Ruegg, M. A., and Brenner, H. R. (2008). The role of nerve- versus muscle-derived factors in mammalian neuromuscular junction formation. J Neurosci 28, 3333–3340PubMedCrossRefGoogle Scholar
  130. Liu, Y., Fields, R. D., Festoff, B. W., and Nelson, P. G. (1994). Proteolytic action of thrombin is required for electrical activity-dependent synapse reduction. Proc Natl Acad Sci U S A 91, 10300–10304PubMedCrossRefGoogle Scholar
  131. Lluri, G., Langlois, G. D., McClellan, B., Soloway, P. D., and Jaworski, D. M. (2006). Tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates neuromuscular junction development via a beta1 integrin-mediated mechanism. J Neurobiol 66, 1365–1377PubMedCrossRefGoogle Scholar
  132. Loeb, J. A. (2003). Neuregulin: an activity-dependent synaptic modulator at the neuromuscular junction. J Neurocytol 32, 649–664PubMedCrossRefGoogle Scholar
  133. Loewi, O. (1921). Über humorale Übertragbarkeit der Herznervenwirkung. Pflügers Archiv, 239–242Google Scholar
  134. Luo, Z., Wang, Q., Dobbins, G. C., Levy, S., Xiong, W. C., and Mei, L. (2003). Signaling complexes for postsynaptic differentiation. J Neurocytol 32, 697–708PubMedCrossRefGoogle Scholar
  135. Lupa, M. T., and Hall, Z. W. (1989). Progressive restriction of synaptic vesicle protein to the nerve terminal during development of the neuromuscular junction. J Neurosci 9, 3937–3945PubMedGoogle Scholar
  136. Lwebuga-Mukasa, J. S., Lappi, S., and Taylor, P. (1976). Molecular forms of acetylcholinesterase from Torpedo californica: their relationship to synaptic membranes. Biochemistry 15, 1425–1434PubMedCrossRefGoogle Scholar
  137. Marnay, A., and Nachmansohn, D. (1937). Cholinesterase in voluntary frog’s muscle. J Physiol 89, 359–367PubMedGoogle Scholar
  138. Marques, M. J., Conchello, J. A., and Lichtman, J. W. (2000). From plaque to pretzel: fold formation and acetylcholine receptor loss at the developing neuromuscular junction. J Neurosci 20, 3663–3675PubMedGoogle Scholar
  139. Martin, P. T., Ettinger, A. J., and Sanes, J. R. (1995). A synaptic localization domain in the synaptic cleft protein laminin beta 2 (s-laminin). Science 269, 413–416PubMedCrossRefGoogle Scholar
  140. Martin, P. T., and Sanes, J. R. (1995). Role for a synapse-specific carbohydrate in agrin-induced clustering of acetylcholine receptors. Neuron 14, 743–754PubMedCrossRefGoogle Scholar
  141. Martin, P. T., and Sanes, J. R. (1997). Integrins mediate adhesion to agrin and modulate agrin signaling. Development 124, 3909–3917PubMedGoogle Scholar
  142. Martin, P. T., Scott, L. J., Porter, B. E., and Sanes, J. R. (1999). Distinct structures and functions of related pre- and postsynaptic carbohydrates at the mammalian neuromuscular junction. Mol Cell Neurosci 13, 105–118PubMedCrossRefGoogle Scholar
  143. Martin, P. T. (2003). Glycobiology of the neuromuscular junction. J Neurocytol 32, 915–929PubMedCrossRefGoogle Scholar
  144. McMahan, U. J. (1990). The agrin hypothesis. Cold Spring Harb Symp Quant Biol 55, 407–418PubMedGoogle Scholar
  145. Miledi, R., Molinoff, P., and Potter, L. T. (1971). Isolation of the cholinergic receptor protein of Torpedo electric tissue. Nature 229(5286), 554–557PubMedCrossRefGoogle Scholar
  146. Miner, J. H., and Sanes, J. R. (1994). Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches. J Cell Biol 127, 879–891PubMedCrossRefGoogle Scholar
  147. Miner, J. H., and Sanes, J. R. (1996). Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol 135, 1403–1413.Google Scholar
  148. Miner, J. H., Patton, B. L., Lentz, S. I., Gilbert, D. J., Snider, W. D., Jenkins, N. A., Copeland, N. G., and Sanes, J. R. (1997). The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterotrimeric laminins 8–11, and cloning of a novel alpha3 isoform. J Cell Biol 137, 685–701.Google Scholar
  149. Miner, J. H., Cunningham, J., and Sanes, J. R. (1998). Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol 143, 1713–1723PubMedCrossRefGoogle Scholar
  150. Misgeld, T., Kummer, T. T., Lichtman, J. W., and Sanes, J. R. (2005). Agrin promotes synaptic differentiation by counteracting an inhibitory effect of neurotransmitter. Proc Natl Acad Sci U S A 102, 11088–11093PubMedCrossRefGoogle Scholar
  151. Moscoso, L. M., Cremer, H., and Sanes, J. R. (1998). Organization and reorganization of neuromuscular junctions in mice lacking neural cell adhesion molecule, tenascin-C, or fibroblast growth factor-5. J Neurosci 18, 1465–1477PubMedGoogle Scholar
  152. Mott, J. D., and Werb, Z. (2004). Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16, 558–564PubMedCrossRefGoogle Scholar
  153. Myllyharju, J., and Kivirikko, K. I. (2004). Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 20, 33–43PubMedCrossRefGoogle Scholar
  154. Nelson, P. G., Lanuza, M. A., Jia, M., Li, M. X., and Tomas, J. (2003). Phosphorylation reactions in activity-dependent synapse modification at the neuromuscular junction during development. J Neurocytol 32, 803–816PubMedCrossRefGoogle Scholar
  155. Nishimune, H., Sanes, J. R., and Carlson, S. S. (2004). A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals. Nature 432, 580–587PubMedCrossRefGoogle Scholar
  156. Nishimune, H., Miner, J. H., and Sanes, J. R. (2005). Roles of individual synaptic laminin chains in presynaptic differentiation at the neuromuscular junction. Paper presented at: Society for Neuroscience. (Washington, DC)Google Scholar
  157. Nitkin, R. M., Smith, M. A., Magill, C., Fallon, J. R., Yao, Y. M., Wallace, B. G., and McMahan, U. J. (1987). Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J Cell Biol 105, 2471–2478PubMedCrossRefGoogle Scholar
  158. Noakes, P. G., Gautam, M., Mudd, J., Sanes, J. R., and Merlie, J. P. (1995). Aberrant differentiation of neuromuscular junctions in mice lacking s-laminin/laminin beta 2. Nature 374, 258–262PubMedCrossRefGoogle Scholar
  159. O’Brien, R. A., Ostberg, A. J., and Vrbova, G. (1978). Observations on the elimination of polyneuronal innervation in developing mammalian skeletal muscle. J Physiol 282, 571–582PubMedGoogle Scholar
  160. O’Brien, R. A., Ostberg, A. J., and Vrbova, G. (1984). Protease inhibitors reduce the loss of nerve terminals induced by activity and calcium in developing rat soleus muscles in vitro. Neuroscience 12, 637–646PubMedCrossRefGoogle Scholar
  161. Ornitz, D. M., and Itoh, N. (2001). Fibroblast growth factors. Genome Biol 2, REVIEWS3005Google Scholar
  162. Ortega, N., and Werb, Z. (2002). New functional roles for non-collagenous domains of basement membrane collagens. J Cell Sci 115, 4201–4214PubMedCrossRefGoogle Scholar
  163. Panzer, J. A., Gibbs, S. M., Dosch, R., Wagner, D., Mullins, M. C., Granato, M., and Balice-Gordon, R. J. (2005). Neuromuscular synaptogenesis in wild-type and mutant zebrafish. Dev Biol 285, 340–357PubMedCrossRefGoogle Scholar
  164. Panzer, J. A., Song, Y., and Balice-Gordon, R. J. (2006). In vivo imaging of preferential motor axon outgrowth to and synaptogenesis at prepatterned acetylcholine receptor clusters in embryonic zebrafish skeletal muscle. J Neurosci 26, 934–947PubMedCrossRefGoogle Scholar
  165. Patton, B. L., Miner, J. H., Chiu, A. Y., and Sanes, J. R. (1997). Distribution and function of laminins in the neuromuscular system of developing, adult, and mutant mice. J Cell Biol 139, 1507–1521PubMedCrossRefGoogle Scholar
  166. Patton, B. L., Cunningham, J. M., Thyboll, J., Kortesmaa, J., Westerblad, H., Edstrom, L., Tryggvason, K., and Sanes, J. R. (2001). Properly formed but improperly localized synaptic specializations in the absence of laminin alpha4. Nat Neurosci 4, 597–604PubMedCrossRefGoogle Scholar
  167. Patton, B. L. (2003). Basal lamina and the organization of neuromuscular synapses. J Neurocytol 32, 883–903PubMedCrossRefGoogle Scholar
  168. Peng, H. B., Xie, H., Rossi, S. G., and Rotundo, R. L. (1999). Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. J Cell Biol 145, 911–921PubMedCrossRefGoogle Scholar
  169. Poberai, M., Savay, G., and Csillik, B. (1972). Function-dependent proteinase activity in the neuromuscular synapse. Neurobiology 2, 1–7PubMedGoogle Scholar
  170. Poberai, M., and Savay, G. (1976). Time course of proteolytic enzyme alterations in the motor end-plates after stimulation. Acta Histochem 57, 44–48PubMedGoogle Scholar
  171. Porter, S., and Froehner, S. C. (1983). Characterization and localization of the Mr = 43,000 proteins associated with acetylcholine receptor-rich membranes. J Biol Chem 258, 10034–10040PubMedGoogle Scholar
  172. Porter, B. E., Weis, J., and Sanes, J. R. (1995). A motoneuron-selective stop signal in the synaptic protein S-laminin. Neuron 14, 549–559PubMedCrossRefGoogle Scholar
  173. Poschl, E., Schlotzer-Schrehardt, U., Brachvogel, B., Saito, K., Ninomiya, Y., and Mayer, U. (2004). Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628PubMedCrossRefGoogle Scholar
  174. Prakash, Y. S., and Sieck, G. C. (1998). Age-related remodeling of neuromuscular junctions on type-identified diaphragm fibers. Muscle Nerve 21, 887–895PubMedCrossRefGoogle Scholar
  175. Pun, S., Sigrist, M., Santos, A. F., Ruegg, M. A., Sanes, J. R., Jessell, T. M., Arber, S., and Caroni, P. (2002). An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles. Neuron 34, 357–370PubMedCrossRefGoogle Scholar
  176. Rafuse, V. F., Polo-Parada, L., and Landmesser, L. T. (2000). Structural and functional alterations of neuromuscular junctions in NCAM-deficient mice. J Neurosci 20, 6529–6539PubMedGoogle Scholar
  177. Reddy, L. V., Koirala, S., Sugiura, Y., Herrera, A. A., and Ko, C. P. (2003). Glial cells maintain synaptic structure and function and promote development of the neuromuscular junction in vivo. Neuron 40, 563–580PubMedCrossRefGoogle Scholar
  178. Redfern, P. A. (1970). Neuromuscular transmission in new-born rats. J Physiol 209, 701–709PubMedGoogle Scholar
  179. Rimer, M. (2003). Neuregulins: primary or secondary signals for the control of synapse-specific gene expression. J Neurocytol 32, 665–675PubMedCrossRefGoogle Scholar
  180. Rimer, M. (2007). Neuregulins at the neuromuscular synapse: past, present, and future. J Neurosci Res 85, 1827–1833PubMedCrossRefGoogle Scholar
  181. Robertson, J. D. (1956a). Some features of the ultrastructure of reptilian skeletal muscle. J Biophys Biochem Cytol 2, 369–380PubMedCrossRefGoogle Scholar
  182. Robertson, J. D. (1956b). The ultrastructure of a reptilian myoneural junction. J Biophys Biochem Cytol 2, 381–394PubMedGoogle Scholar
  183. Robitaille, R., Adler, E. M., and Charlton, M. P. (1990). Strategic location of calcium channels at transmitter release sites of frog neuromuscular synapses. Neuron 5, 773–779PubMedCrossRefGoogle Scholar
  184. Robitaille, R., Adler, E. M., and Charlton, M. P. (1993a). Calcium channels and calcium-gated potassium channels at the frog neuromuscular junction. J Physiol Paris 87, 15–24PubMedCrossRefGoogle Scholar
  185. Robitaille, R., Garcia, M. L., Kaczorowski, G. J., and Charlton, M. P. (1993b). Functional colocalization of calcium and calcium-gated potassium channels in control of transmitter release. Neuron 11, 645–655PubMedCrossRefGoogle Scholar
  186. Rosenheimer, J. L., and Smith, D. O. (1985). Differential changes in the end-plate architecture of functionally diverse muscles during aging. J Neurophysiol 53, 1567–1581PubMedGoogle Scholar
  187. Rosenthal, J. L., and Taraskevich, P. S. (1977). Reduction of multiaxonal innervation at the neuromuscular junction of the rat during development. J Physiol 270, 299–310PubMedGoogle Scholar
  188. Rotundo, R. L. (2003). Expression and localization of acetylcholinesterase at the neuromuscular junction. J Neurocytol 32, 743–766PubMedCrossRefGoogle Scholar
  189. Rotundo, R. L., Ruiz, C. A., Marrero, E., Kimbell, L. M., Rossi, S. G., Rosenberry, T., Darr, A., and Tsoulfas, P. (2008). Assembly and regulation of acetylcholinesterase at the vertebrate neuromuscular junction. Chem Biol InteractGoogle Scholar
  190. Ruegg, M. A., Tsim, K. W., Horton, S. E., Kroger, S., Escher, G., Gensch, E. M., and McMahan, U. J. (1992). The agrin gene codes for a family of basal lamina proteins that differ in function and distribution. Neuron 8, 691–699PubMedCrossRefGoogle Scholar
  191. Salpeter, M. M., and Loring, R. H. (1985). Nicotinic acetylcholine receptors in vertebrate muscle: properties, distribution and neural control. Prog Neurobiol 25, 297–325PubMedCrossRefGoogle Scholar
  192. Sanes, J. R., Marshall, L. M., and McMahan, U. J. (1978). Reinnervation of muscle fiber basal lamina after removal of myofibers. Differentiation of regenerating axons at original synaptic sites. J Cell Biol 78, 176–198PubMedCrossRefGoogle Scholar
  193. Sanes, J. R., and Hall, Z. W. (1979). Antibodies that bind specifically to synaptic sites on muscle fiber basal lamina. J Cell Biol 83, 357–370PubMedCrossRefGoogle Scholar
  194. Sanes, J. R., and Cheney, J. M. (1982). Lectin binding reveals a synapse-specific carbohydrate in skeletal muscle. Nature 300, 646–647PubMedCrossRefGoogle Scholar
  195. Sanes, J. R., Schachner, M., and Covault, J. (1986). Expression of several adhesive macromolecules (N-CAM, L1, J1, NILE, uvomorulin, laminin, fibronectin, and a heparan sulfate proteoglycan) in embryonic, adult, and denervated adult skeletal muscle. J Cell Biol 102, 420–431PubMedCrossRefGoogle Scholar
  196. Sanes, J. R., Engvall, E., Butkowski, R., and Hunter, D. D. (1990). Molecular heterogeneity of basal laminae: isoforms of laminin and collagen IV at the neuromuscular junction and elsewhere. J Cell Biol 111, 1685–1699PubMedCrossRefGoogle Scholar
  197. Sanes, J. R., Apel, E. D., Gautam, M., Glass, D., Grady, R. M., Martin, P. T., Nichol, M. C., and Yancopoulos, G. D. (1998). Agrin receptors at the skeletal neuromuscular junction. Ann N Y Acad Sci 841, 1–13PubMedCrossRefGoogle Scholar
  198. Sanes, J. R., and Lichtman, J. W. (1999). Development of the vertebrate neuromuscular junction. Annu Rev Neurosci 22, 389–442PubMedCrossRefGoogle Scholar
  199. Sanes, J. R., and Lichtman, J. W. (2001). Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2, 791–805PubMedCrossRefGoogle Scholar
  200. Sanes, J. R. (2003). The basement membrane/basal lamina of skeletal muscle. J Biol Chem 278, 12601–12604PubMedCrossRefGoogle Scholar
  201. Santos, A. F., and Caroni, P. (2003). Assembly, plasticity and selective vulnerability to disease of mouse neuromuscular junctions. J Neurocytol 32, 849–862PubMedCrossRefGoogle Scholar
  202. Schoch, S., and Gundelfinger, E. D. (2006). Molecular organization of the presynaptic active zone. Cell Tissue Res 326, 379–391PubMedCrossRefGoogle Scholar
  203. Schumacher, M., Camp, S., Maulet, Y., Newton, M., MacPhee-Quigley, K., Taylor, S. S., Friedmann, T., and Taylor, P. (1986). Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence. Nature 319, 407–409PubMedCrossRefGoogle Scholar
  204. Schwander, M., Shirasaki, R., Pfaff, S. L., and Muller, U. (2004). Beta1 integrins in muscle, but not in motor neurons, are required for skeletal muscle innervation. J Neurosci 24, 8181–8191PubMedCrossRefGoogle Scholar
  205. Scott, L. J., Bacou, F., and Sanes, J. R. (1988). A synapse-specific carbohydrate at the neuromuscular junction: association with both acetylcholinesterase and a glycolipid. J Neurosci 8, 932–944PubMedGoogle Scholar
  206. Scott, L. J., Balsamo, J., Sanes, J. R., and Lilien, J. (1990). Synaptic localization and neural regulation of an N-acetylgalactosaminyl transferase in skeletal muscle. J Neurosci 10, 346–350PubMedGoogle Scholar
  207. Sealock, R., Wray, B. E., and Froehner, S. C. (1984). Ultrastructural localization of the Mr 43,000 protein and the acetylcholine receptor in Torpedo postsynaptic membranes using monoclonal antibodies. J Cell Biol 98, 2239–2244PubMedCrossRefGoogle Scholar
  208. Sheridan, M. N. (1965). The Fine Structure of the Electric Organ of Torpedo Marmorata. J Cell Biol 24, 129–141PubMedCrossRefGoogle Scholar
  209. Sigoillot, M., Lambergeon, M., Bourgeois, F., and Legay, C. (2007). The role of ColQ, a specific collagen in the postsynaptic organization of the neuromuscular junction. Paper presented at: Society for Neuroscience. (San Diego, CA)Google Scholar
  210. Slater, C. R. (1982). Postnatal maturation of nerve-muscle junctions in hindlimb muscles of the mouse. Dev Biol 94, 11–22PubMedCrossRefGoogle Scholar
  211. Slater, C. R., Lyons, P. R., Walls, T. J., Fawcett, P. R., and Young, C. (1992). Structure and function of neuromuscular junctions in the vastus lateralis of man. A motor point biopsy study of two groups of patients. Brain 115 (Pt 2), 451–478PubMedGoogle Scholar
  212. Slater, C. R. (2003). Structural determinants of the reliability of synaptic transmission at the vertebrate neuromuscular junction. J Neurocytol 32, 505–522PubMedCrossRefGoogle Scholar
  213. Smirnov, S. P., Barzaghi, P., McKee, K. K., Ruegg, M. A., and Yurchenco, P. D. (2005). Conjugation of LG domains of agrins and perlecan to polymerizing laminin-2 promotes acetylcholine receptor clustering. J Biol Chem 280, 41449–41457PubMedCrossRefGoogle Scholar
  214. Steinbach, J. H. (1981). Neuromuscular junctions and alpha-bungarotoxin-binding sites in denervated and contralateral cat skeletal muscles. J Physiol 313, 513–528PubMedGoogle Scholar
  215. Sternlicht, M. D., and Werb, Z. (2001). How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17, 463–516PubMedCrossRefGoogle Scholar
  216. Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007). The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178PubMedCrossRefGoogle Scholar
  217. Storms, S. D., Kim, A. C., Tran, B. H., Cole, G. J., and Murray, B. A. (1996). NCAM-mediated adhesion of transfected cells to agrin. Cell Adhes Commun 3, 497–509PubMedCrossRefGoogle Scholar
  218. Strochlic, L., Cartaud, A., and Cartaud, J. (2005). The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions. Bioessays 27, 1129–1135PubMedCrossRefGoogle Scholar
  219. Südhof, T. C. (2004). The synaptic vesicle cycle. Annu Rev Neurosci 27, 509–547PubMedCrossRefGoogle Scholar
  220. Sunesen, M., and Changeux, J. P. (2003). Transcription in neuromuscular junction formation: who turns on whom? J Neurocytol 32, 677–684PubMedCrossRefGoogle Scholar
  221. Tai, K., Bond, S. D., MacMillan, H. R., Baker, N. A., Holst, M. J., and McCammon, J. A. (2003). Finite element simulations of acetylcholine diffusion in neuromuscular junctions. Biophys J 84, 2234–2241PubMedCrossRefGoogle Scholar
  222. Takahashi, T., Nakajima, Y., Hirosawa, K., Nakajima, S., and Onodera, K. (1987). Structure and physiology of developing neuromuscular synapses in culture. J Neurosci 7, 473–481PubMedGoogle Scholar
  223. Tello, J.F. (1907). Dègèneration et règèneration des plaques motrices après la section des nerfs. Trav Lab Recherches Biol 5, 117–149Google Scholar
  224. Todd, K. J., Auld, D. S., and Robitaille, R. (2007). Neurotrophins modulate neuron-glia interactions at a vertebrate synapse. Eur J Neurosci 25, 1287–1296PubMedCrossRefGoogle Scholar
  225. Trimble, W. S., Cowan, D. M., and Scheller, R. H. (1988). VAMP-1: a synaptic vesicle-associated integral membrane protein. Proc Natl Acad Sci U S A 85, 4538–4542PubMedCrossRefGoogle Scholar
  226. Umemori, H., Linhoff, M. W., Ornitz, D. M., and Sanes, J. R. (2004). FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118, 257–270PubMedCrossRefGoogle Scholar
  227. Urbano, F. J., Rosato-Siri, M. D., and Uchitel, O. D. (2002). Calcium channels involved in neurotransmitter release at adult, neonatal and P/Q-type deficient neuromuscular junctions (Review). Mol Membr Biol 19, 293–300PubMedCrossRefGoogle Scholar
  228. Usdin, T. B., and Fischbach, G. D. (1986). Purification and characterization of a polypeptide from chick brain that promotes the accumulation of acetylcholine receptors in chick myotubes. J Cell Biol 103, 493–507PubMedCrossRefGoogle Scholar
  229. Vaisanen, M. R., Vaisanen, T., and Pihlajaniemi, T. (2004). The shed ectodomain of type XIII collagen affects cell behaviour in a matrix-dependent manner. Biochem J 380, 685–693PubMedCrossRefGoogle Scholar
  230. Valenstein, E. S. (2002). The discovery of chemical neurotransmitters. Brain Cogn 49, 73–95PubMedCrossRefGoogle Scholar
  231. Valenzuela, D. M., Stitt, T. N., DiStefano, P. S., Rojas, E., Mattsson, K., Compton, D. L., Nunez, L., Park, J. S., Stark, J. L., Gies, D. R., and et al. (1995). Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15, 573–584PubMedCrossRefGoogle Scholar
  232. VanSaun, M., and Werle, M. J. (2000). Matrix metalloproteinase-3 removes agrin from synaptic basal lamina. J Neurobiol 43, 140–149PubMedCrossRefGoogle Scholar
  233. VanSaun, M., Herrera, A. A., and Werle, M. J. (2003). Structural alterations at the neuromuscular junctions of matrix metalloproteinase 3 null mutant mice. J Neurocytol 32, 1129–1142PubMedCrossRefGoogle Scholar
  234. Vogel, Z., Christian, C. N., Vigny, M., Bauer, H. C., Sonderegger, P., and Daniels, M. P. (1983). Laminin induces acetylcholine receptor aggregation on cultured myotubes and enhances the receptor aggregation activity of a neuronal factor. J Neurosci 3, 1058–1068PubMedGoogle Scholar
  235. Wallace, B. G., Nitkin, R. M., Reist, N. E., Fallon, J. R., Moayeri, N. N., and McMahan, U. J. (1985). Aggregates of acetylcholinesterase induced by acetylcholine receptor-aggregating factor. Nature 315, 574–577PubMedCrossRefGoogle Scholar
  236. Werle, M. J., and VanSaun, M. (2003). Activity dependent removal of agrin from synaptic basal lamina by matrix metalloproteinase 3. J Neurocytol 32, 905–913PubMedCrossRefGoogle Scholar
  237. Wilczynski, G. M., Konopacki, F. A., Wilczek, E., Lasiecka, Z., Gorlewicz, A., Michaluk, P., Wawrzyniak, M., Malinowska, M., Okulski, P., Kolodziej, L. R., et al. (2008). Important role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol 180, 1021–1035PubMedCrossRefGoogle Scholar
  238. Witzemann, V. (2006). Development of the neuromuscular junction. Cell Tissue Res 326, 263–271PubMedCrossRefGoogle Scholar
  239. Wokke, J. H., Jennekens, F. G., van den Oord, C. J., Veldman, H., Smit, L. M., and Leppink, G. J. (1990). Morphological changes in the human end plate with age. J Neurol Sci 95, 291–310PubMedCrossRefGoogle Scholar
  240. Wood, S. J., and Slater, C. R. (2001). Safety factor at the neuromuscular junction. Prog Neurobiol 64, 393–429PubMedCrossRefGoogle Scholar
  241. Wyatt, R. M., and Balice-Gordon, R. J. (2003). Activity-dependent elimination of neuromuscular synapses. J Neurocytol 32, 777–794PubMedCrossRefGoogle Scholar
  242. Yang, X., Li, W., Prescott, E. D., Burden, S. J., and Wang, J. C. (2000). DNA topoisomerase IIbeta and neural development. Science 287, 131–134PubMedCrossRefGoogle Scholar
  243. Yang, X., Arber, S., William, C., Li, L., Tanabe, Y., Jessell, T. M., Birchmeier, C., and Burden, S. J. (2001). Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron 30, 399–410PubMedCrossRefGoogle Scholar
  244. Young, S. H., and Poo, M. M. (1983). Spontaneous release of transmitter from growth cones of embryonic neurones. Nature 305, 634–637PubMedCrossRefGoogle Scholar
  245. Yurchenco, P. D., Amenta, P. S., and Patton, B. L. (2004). Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol 22, 521–538PubMedCrossRefGoogle Scholar
  246. Zhang, J., Lefebvre, J. L., Zhao, S., and Granato, M. (2004). Zebrafish unplugged reveals a role for muscle-specific kinase homologs in axonal pathway choice. Nat Neurosci 7, 1303–1309PubMedCrossRefGoogle Scholar
  247. Zoubine, M. N., Ma, J. Y., Smirnova, I. V., Citron, B. A., and Festoff, B. W. (1996). A molecular mechanism for synapse elimination: novel inhibition of locally generated thrombin delays synapse loss in neonatal mouse muscle. Dev Biol 179, 447–457PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Anatomy and NeurobiologyVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations