Journal of Neurocytology

, Volume 32, Issue 5–8, pp 863–881 | Cite as

The relationship of neuromuscular synapse elimination to synaptic degeneration and pathology: Insights from WldS and other mutant mice

  • Thomas H. Gillingwater
  • Richard R. RibchesterEmail author


Neuromuscular synapse elimination, Wallerian degeneration and peripheral neuropathies are not normally considered as related phenomena. However, recent studies of mutant and transgenic mice, particularly the WldS mutant—in which orthograde degeneration is delayed following axotomy—suggest that re-evaluation of possible links between natural, traumatic and pathogenic regression of synapses may be warranted. During developmental synapse elimination from polyneuronally innervated junctions, some motor nerve terminals progressively and asynchronously vacate motor endplates. A form of asynchronous synapse withdrawal, strongly resembling synapse elimination, also occurs from mononeuronally-innervated motor endplates following axotomy in young adult WldS mutant mice. A similar pattern is observed in skeletal muscles of several neuropathic mutants, including mouse models of dying-back neuropathies, motor neuron disease and—remarkably—models of neurodegenerative diseases such as Huntington's and Alzheimer's diseases. Taken together with recent analysis of synaptic remodelling at neuromuscular junctions in Drosophila, a strong candidate for a common regulatory mechanism in these diverse conditions is one based on protein ubiquitination/deubiquitination. Axotomised neuromuscular junctions in WldS mutant mice offer favourable experimental opportunities for examining developmental mechanisms of synaptic regression, that may also benefit our understanding of how degeneration in the synaptic compartment of a neuron is initiated, and its role in progressive, whole-cell neuronal degeneration.


Neuropathy Neurodegenerative Disease Motor Neuron Peripheral Neuropathy Neuromuscular Junction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. AIRAKSINEN, M. S. & SAARMA, M. (2002) The GDNF family: Signalling, biological functions and therapeutic value. Nature Reviews Neuroscience 3, 38–394.PubMedGoogle Scholar
  2. BALICE-GORDON, R. J., CHUA, C. K., NELSON, C. C. & LICHTMAN, J. W. (1993) Gradual loss of synaptic cartels precedes axon withdrawal at developing neuromuscular junctions. Neuron 11, 80–815.PubMedGoogle Scholar
  3. BALICE-GORDON, R. J. & LICHTMAN, J. W. (1994) Long-term synapse loss induced by focal blockade of postsynaptic receptors. Nature 372, 51–524.PubMedGoogle Scholar
  4. BALICE-GORDON, R. J., SMITH, D. B., GOLDMAN, J., CORK, L. C., SHIRLEY, A., COPE, T. C. & PINTER, M. J. (2000) Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease. Annals of Neurology 47, 59–605.PubMedGoogle Scholar
  5. BARRY, J. A. & RIBCHESTER, R. R. (1995) Persistent polyneuronal innervation in partially denervated rat muscle after reinnervation and recovery from prolonged nerve conduction block. Journal of Neuroscience 15, 632–6339.PubMedGoogle Scholar
  6. BENOIT, P. & CHANGEUX, J. P. (1975) Consequences of tenotomy on the evolution of multiinnervation in developing rat soleus muscle. Brain Research 99, 35–358.PubMedGoogle Scholar
  7. BETZ, W. J., CALDWELL, J. H. & RIBCHESTER, R. R. (1980) The effects of partial denervation at birth on the development of muscle fibres and motor units in rat lumbrical muscle. Journal of Physiology 303, 26–279.PubMedGoogle Scholar
  8. BETZ, W. & SAKMANN, B. (1973) Effects of proteolytic enzymes on function and structure of frog neuromuscular junctions. Journal of Physiology 230, 67–688.PubMedGoogle Scholar
  9. BIXBY, J. L. (1981) Ultrastructural observations on synapse elimination in neonatal rabbit skeletal muscle. Journal of Neurocytology 10, 8–100.PubMedGoogle Scholar
  10. BOEKE, J. (1916) Studien zur nervenregeneration. i di regeneration der motorischen nerven elemente und die regeneration der nerven der muskelspindeln. Verhandlingen. Koninkonen. Akadamie.Wetenschaffen (Amsterdam) 18, –120.Google Scholar
  11. BROWN, M. C., HOPKINS, W. G. & KEYNES, R. J. (1982) Short-and long-term effects of paralysis on the motor innervation of two different neonatal mouse muscles. Journal of Physiology 329, 43–450.PubMedGoogle Scholar
  12. BROWN, M. C., JANSEN, J. K. & VAN ESSEN, D. (1976) Polyneuronal innervation of skeletal muscle in new-born rats and its elimination during maturation. Journal of Physiology 261, 38–422.PubMedGoogle Scholar
  13. BUFFELLI, M., BURGESS, R. W., FENG, G., LOBE, C. G., LICHTMAN, J. W. & SANES, J. R. (2003) Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition. Nature 424, 43–434.PubMedGoogle Scholar
  14. CADAVID, A. L. M., GINZEL, A. & FISCHER, J. A. (2000) The function of the Drosophila Fat facets deubiquitinating enzyme in limiting photoreceptor cell number is intimately associated with endocytosis. Development 127, 172–1736.PubMedGoogle Scholar
  15. CALLAWAY, E. M., SOHA, J. M. & VAN ESSEN, D. C. (1987) Competition favouring inactive over active motor neurons during synapse elimination. Nature 328, 42–426.PubMedGoogle Scholar
  16. CAVANAGH, J. B. (1964) The significance of the 'dying back' process in experimental andhumanneurological disease. International Reviews in Experimental Pathology 3, 21–267.Google Scholar
  17. CHANG, Q. & BALICE-GORDON, R. J. (1997) Nip and tuck at the neuromuscular junction: A role for proteases in developmental synapse elimination. Bioessays 19, 27–275.PubMedGoogle Scholar
  18. CHEN, X., ZHANG, B. & FISCHER, J. A. (2002) A specific protein substrate for a deubiquitinating enzyme: Liquid facets is the substrate of fat facets. Genes and Development 16, 28–294.PubMedGoogle Scholar
  19. CHIBA, A., KUSUNOKI, S., SHIMIZU, T. & KANAZAWA, I. (1992) Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Annals of Neurology 31, 67–679.PubMedGoogle Scholar
  20. CIECHANOVER, A., HELLER, H., ELIAS, S., HAAS, A. L. & HERSHKO, A. (1980) ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proceedings of the National Academy of Sciences USA 77, 136–1368.Google Scholar
  21. CLINE, H. (2003) Synaptic plasticity: Importance of proteasome-mediated protein turnover. Current Biology 13, R51–R516.PubMedGoogle Scholar
  22. COLEMAN, M. P. & PERRY, V. H. (2002) Axon pathology in neurological disease: A neglected therapeutic target. Trends in Neurosciences 25, 53–537.PubMedGoogle Scholar
  23. COLMAN, H., NABEKURA, J. & LICHTMAN, J. W. (1997) Alterations in synaptic strength preceding axon withdrawal. Science 275, 35–361.PubMedGoogle Scholar
  24. CONAWAY, R. C., BROWER, C. S. & CONAWAY, J. W. (2002) Emerging roles of ubiquitin in transcription regulation. Science 296, 125–1258.PubMedGoogle Scholar
  25. CONFORTI, L., TARLTON, A., MACK, T. G., MI, W., BUCKMASTER, E. A., WAGNER, D., PERRY, V. H. & COLEMAN, M. P. (2000) AUfd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slowWallerian degeneration (WldS) mouse. Proceedings of the National Academy of Sciences USA 97, 1137–11382.Google Scholar
  26. CONNOLD, A. L. & VRBOVA, G. (1994) Neuromuscular contacts of expanded motor units in rat soleus muscles are rescued by leupeptin. Neuroscience 63, 32–338.PubMedGoogle Scholar
  27. COSTANZO, E. M., BARRY, J. A. & RIBCHESTER, R. R. (1999) Co-regulation of synaptic efficacy at stable polyneuronally innervated neuromuscular junctions in reinnervated rat muscle. Journal of Physiology 521, 36–374.PubMedGoogle Scholar
  28. COSTANZO, E. M., BARRY, J. A. & RIBCHESTER, R. R. (2000) Competition at silent synapses in reinnervated skeletal muscle. Nature Neuroscience 3, 69–700.PubMedGoogle Scholar
  29. CREGAN, S. P., MACLAURIN, J. G., CRAIG, C. G., ROBERTSON, G. S., NICHOLSON, D. W., PARK, D. S. & SLACK, R. S. (1999) Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. Journal of Neuroscience 19, 786–7869.PubMedGoogle Scholar
  30. DECKWERTH, T. L. & JOHNSON, E. M. (1994) Neurites can remain viable after the destruction of the neuronal soma by programmed cell death. Developmental Biology 165, 6–72.PubMedGoogle Scholar
  31. DIANTONIO, A., HAGHIGHI, A. P., PORTMAN, S. L., LEE, J. D., AMARANTO, A. M. & GOODMAN, C. S. (2001) Ubiquitin-dependent mechanisms regulate synaptic growth and function. Nature 412, 44–452.PubMedGoogle Scholar
  32. EHLERS, M. D. (2003) Ubiquitin and synaptic dysfunction: Ataxic mice highlight new common themes in neurological disease. Trends in Neurosciences 26, –7.PubMedGoogle Scholar
  33. FENG, G., MELLOR, R. H., BERNSTEIN, M., KELLERPECK, C., NGUYEN, Q. T., WALLACE, M., NERBONNE, J. M., LICHTMAN J. W, & SANES, J. R. (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 4–51.PubMedGoogle Scholar
  34. FERNANDO, F. S., CONFORTI, L., TOSI, S., SMITH, A. D. & COLEMAN, M. P. (2002) Human homologue of a gene mutated in the slow Wallerian degeneration (C57BL/Wld(s)) mouse. Gene 284, 2–29.PubMedGoogle Scholar
  35. FERRI, A., SANES, J. R., COLEMAN, M. P., CUNNINGHAM, J. M. & KATO, A. C. (2003) Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Current Biology 13, 66–673.PubMedGoogle Scholar
  36. FESTOFF, B. W., SUO, Z. & CITRON, B. A. (2001) Plasticity and stabilisation of neuromuscular and CNS synapses: Interactions between thrombin protease signalling pathways and tissue transglutaminase. International Reviews in Cytology 211, 15–177.Google Scholar
  37. FISCHER, J. A. & OVERSTREET, E. (2002) Fat facets does a highwire act at the synapse. Bioessays 24, 1–16.PubMedGoogle Scholar
  38. FLADBY, T. & JANSEN, J. K. (1987) Postnatal loss of synaptic terminals in the partially denervated mouse soleus muscle. Acta Physiologica Scandinavica 129, 23–246.PubMedGoogle Scholar
  39. FRANK, E. (1997) Synapse elimination: for nerves it's all or nothing. Science 275, 32–325.PubMedGoogle Scholar
  40. FREY, D., SCHNEIDER, C., XU, L., BORG, J., SPOOREN, W. & CARONI, P. (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. Journal of Neuroscience 20, 253–2542.PubMedGoogle Scholar
  41. GAN, W.-B., KWON, E., FENG, G., SANES, J. R. & LICHTMAN, J. W. (2003) Synaptic dynamism measured over minutes to months: age-dependent decline in an autonomic ganglion. Nature Neuroscience 6, 95–960.PubMedGoogle Scholar
  42. GEORGE, J. M. (2001) The synucleins. Genome Biology 3, reviews 3002.–3002.6.Google Scholar
  43. GILLINGWATER, T. H. & RIBCHESTER, R. R. (2001) Compartmental neurodegeneration and synaptic plasticity in the WldS mutant mouse. Journal of Physiology 534, 62–639.PubMedGoogle Scholar
  44. GILLINGWATER, T. H., THOMSON, D., MACK, T. G. A., SOFFIN, E. M., MATTISON, R. J., COLEMAN, M. P. & RIBCHESTER, R. R. (2002) Age-dependent synapse withdrawal at axotomised neuromuscular junctions in WldS mutant and Ube4b/Nmnat transgenic mice. Journal of Physiology 543, 73–755.PubMedGoogle Scholar
  45. GILLINGWATER, T. H., INGHAM, C. A., COLEMAN, M. P. & RIBCHESTER, R. R. (2003a) Ultrastructural correlates of synapse withdrawal at axotomized neuromuscular junctions in mutant and transgenic mice expressing the Wld gene. Journal of Anatomy 203, 26– 276.PubMedGoogle Scholar
  46. GILLINGWATER, T. H., COLEMAN, M. P. & RIBCHESTER, R. R. (2003b) Asynchronous synapse withdrawal induced by axotomy in Wld mutant mice expressing fluorescent protein in single motor units. Journal of Physiology 548P, 049.Google Scholar
  47. GILLINGWATER, T. H., THOMSON, D. & RIBCHESTER, R. R. (2004) Myo-GDNF increases non-functional poly innervation of reinnervated mouse muscle. Neuroreport, In Press.Google Scholar
  48. GLICKMAN, M. H. & CIECHANOVER, A. (2002) The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiological Reviews 82, 37–428.PubMedGoogle Scholar
  49. GUTH, L., ZHANG, Z. & STEWARD, O. (1999) The unique histopathological responses of the injured spinal cord. Implications for neuroprotective therapy. Annals of the New York Academy of Sciences 890, 36–384.PubMedGoogle Scholar
  50. HEGDE, A. N. & DIANTONIO, A. (2002) Ubiquitin and the synapse. Nature Reviews Neuroscience 3, 85–861.PubMedGoogle Scholar
  51. HERSHKO, A., CIECHANOVER, A., HELLER, H., HAAS, A. L. & ROSE, I. A. (1980) Proposed role ofATP in protein breakdown: Conjugation of protein with multiple chains of the polypeptide of ATP-dependent proteolysis. Procedings of the National Academy of Sciences USA 77, 178–1786.Google Scholar
  52. HICKE, L. (2001) Protein regulation by monoubiquitin. Nature Reviews Molecular Cell Biology 2, 19–201.PubMedGoogle Scholar
  53. HOFFMAN, H. (1953) The persistence of hyperneurotized end-plates in mammalian muscles. Journal of Comparative Neurology 99, 33–345.PubMedGoogle Scholar
  54. HUANG, Y., BAKER, R. T. & FISCHER-VIZE, J. A. (1995) Control of cell fate by a deubiquitinating enzyme encoded by the fat facets gene. Science 270, 182– 1831.PubMedGoogle Scholar
  55. HUDSON, C. S., DESHPANDE, S. S. & ALBUQUERQUE, E. X. (1984) Consequences of axonal transport blockade by batrachotoxin on mammalian neuromuscular junction. III. An ultrastructural study. Brain Research 296, 31–332.PubMedGoogle Scholar
  56. ILYAS, A. A., MITHEN, F. A., DALAKAS, M. C., CHEN, Z. W. & COOK, S. D. (1992) Antibodies to acidic glycolipids in Guillan-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. Journal of the Neurological Sciences 107, 11–121.PubMedGoogle Scholar
  57. IWAI, A. (2000) Properties of NACP/alpha-synuclein and its role in Alzheimer's disease. Biochim. Biophys. Acta. 26, 9–109.Google Scholar
  58. JENNINGS, C. (1994) Developmental neurobiology. Death of a synapse. Nature 372, 49–499.PubMedGoogle Scholar
  59. JIRMANOVA, I. (1975) Ultrastructure of motor end-plates during pharmacologically-induced degeneration and subsequent regeneration of skeletal muscle. Journal of Neurocytology 4, 14–155.PubMedGoogle Scholar
  60. KAISER, P., FLICK, K., WITTENBERG, C. & REED, S. I. (2000) Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. Cell 102, 30–314.PubMedGoogle Scholar
  61. KASTHURI, N. & LICHTMAN, J. W. (2003) The role of neuronal identity in synaptic competition. Nature 424, 42–430.PubMedGoogle Scholar
  62. KATZ, B. (1996) Neural transmitter release: From quantal secretion to exocytosis and beyond. The Fenn Lecture. Journal of Neurocytology 25, 67–686.PubMedGoogle Scholar
  63. KAWABUCHI, M., CINTRA, W. M., DESHPANDE, S. S. & ALBUQUERQUE, E. X. (1991) Morphological and electrophysiological study of distal motor nerve fiber degeneration and sprouting after irreversible cholinesterase inhibition. Synapse 8, 21–228.PubMedGoogle Scholar
  64. KELLER-PECK, C. R., WALSH, M. K., GAN, W. B., FENG, G., SANES, J. R. & LICHTMAN, J. W. (2001a) Asynchronous synapse elimination in neonatal motor units: Studies using GFP transgenic mice. Neuron 31, 38–394.PubMedGoogle Scholar
  65. KELLER-PECK, C. R., FENG, G., SANES, J. R., YAN, Q., LICHTMAN, J. W. & SNIDER, W. D (2001b) Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction. Journal of Neuroscience 21, 613–6146.PubMedGoogle Scholar
  66. KHERIF, S., DEHAUPAS, M., LAFUMA, C., FARDEAU, M. & ALAMEDDINE, H. S. (1998) Matrix metalloproteinases MMP-2 and MMP-9 in denervated muscle and injured nerve. Neuropathology and Applied Neurobiology 24, 30–319.PubMedGoogle Scholar
  67. KIAEI, M., LORENZL, S. & BEAL, M. F. (2002) Life extension in a transgenic animal model of amyotrophic lateral sclerosis by crossing to matrix-metalloproteinase-9 null mice. Program No. 789.6. 2002 Abstract Viewer, Washington, DC; Society for Neuroscience, 2002. CD-ROM.Google Scholar
  68. KOEGL, M., HOPPE, T., SCHLENKER, S., ULRICH, H. D., MAYER, T. U. & JENTSCH, S. (1999) Anovel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96, 63–644.PubMedGoogle Scholar
  69. KOPP, D. M., PERKEL, D. J. & BALICE-GORDON, R. J. (2000) Disparity in neurotransmitter release probability amongcompeting inputs during neuromuscular synapse elimination. Journal of Neuroscience 20, 877–8779.PubMedGoogle Scholar
  70. KORNELIUSSEN, H & JANSEN, J. K. S. (1976) Morphological aspects of the elimination of polyneuronal innervation of skeletal muscle fibres in newborn rats. Journal of Neurocytology 5, 59–604.PubMedGoogle Scholar
  71. KOTZBAUER, P. T., TROJANOWSK, J. Q. & LEE, V. M. (2001) Lewybody pathology in Alzheimer's disease. Journal of Molecular Neuroscience 17, 22–232.PubMedGoogle Scholar
  72. KÑHNE, W. (1888) Croonian Lecture: On the origin and causation of vital movement. Proceedings of the Royal Society, Series B 44, 42–448.Google Scholar
  73. KUIDA, K. (2000) Caspase-9. International Journal of Biochemistry and Cell Biology 32, 12–124.PubMedGoogle Scholar
  74. LANUZA, M. A., GARCIA, N., SANTAFE, M., NELSON, P. G., FENOLL-BRUNET, M. R. & TOMAS, J. (2001) Pertussis toxin-sensitive G-protein and protein kinase C activity are involved in normal synapse elimination in the neonatal rat muscle. Journal of Neuroscience Research 63, 33–340.PubMedGoogle Scholar
  75. LAYFIELD, R., ALBAN, A., MAYER, R. J. & LOWE, J. (2001) The ubiquitin protein catabolic disorders. Neuropathology and Applied Neurobiology 27, 17–179.PubMedGoogle Scholar
  76. LEBLANC, A., LIU, H., GOODYER, C., BERGERON, C. & HAMMOND, J. (1999) Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and alzheimer's disease. Journal of Biological Chemistry 274, 2342–23436.PubMedGoogle Scholar
  77. LINGBECK, J. M., TRAUSCH-AZAR, J. S., CIECHANOVER, A. & SCHWARTZ, A. L. (2003) Determinants of nuclear and cytoplasmic ubiquitinmediated degradation of MyoD. Journal of Biological Chemistry 278, 181–1823.PubMedGoogle Scholar
  78. LIU, Y., FIELDS, R. D., FESTOFF, B. W. & NELSON, P. G. (1994) Proteolytic action of thrombin is required for electrical activity-dependent synapse reduction. Proceedings of the National Academy of Sciences USA 91, 1030–10304.Google Scholar
  79. LOTHARIUS, J. & BRUNDIN, P. (2002) Pathogenesis of Parkinson's disease: Dopamine, vesicles and alphasynuclein. Nature Reviews Neuroscience 3, 93–942.PubMedGoogle Scholar
  80. LUDWIN, S. K. & BISBY, M. A. (1992) Delayed wallerian degeneration in the central nervous system of Ola mice: An ultrastructural study. Journal of the Neurological Sciences 109, 14–147.PubMedGoogle Scholar
  81. LUNN, E. R., PERRY, V. H., BROWN, M. C., ROSEN, H. & GORDON, S. (1989) Absence of wallerian degeneration does not hinder regeneration in peripheral nerve. European Journal of Neuroscience 1, 2–33.PubMedGoogle Scholar
  82. MACK. T. G. A., REINER, M., BEIROWSKI, B., MI, W., EMANUELLI, M., WAGNER, D., THOMSON, D., GILLINGWATER, T., COURT, F., CONFORTI, L., SHAMA FERNANDO, F., TARLTON, A., ANDRESSEN, C., ADDICKS, K., MAGNI, G., RIBCHESTER, R. R., PERRY, V. H. & COLEMAN, M. P. (2001) Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nature Neuroscience 4, 119–1206.Google Scholar
  83. MASELLI, R. A., WOLLMAN, R. L., LEUNG, C., DISTAD, B., PALOMBI, S., RICHMAN, D. P., SALAZAR-GRUESO, E. F. & ROOS, R. P. (1993) Neuromuscular transmission in amyotrophic lateral sclerosis. Muscle & Nerve 16, 119–1203.Google Scholar
  84. MATTSON, M. P., PARTIN, J. & BEGLEY, J. G. (1998a) Amyloid ?-peptide induces apoptosis-related events in synapses and dendrites. Brain Research 807, 16– 176.PubMedGoogle Scholar
  85. MATTSON, M. P., KELLER, J. N. & BEGLEY, J. G. (1998b) Evidence for synaptic apoptosis. Experimental Neurology 153, 3–48.PubMedGoogle Scholar
  86. MATTSON, M. P., PEDERSEN, W. A., DUAN, W., CULMSEE, C. & CAMANDOLA, S. (1999) Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases. Annals of the New York Academy of Sciences 893, 15–175.PubMedGoogle Scholar
  87. MCARDLE, J. J. (1975) Complex end-plate potentials at the regenerating neuromuscular junction of the rat. Experimental Neurology 49, 62–638.PubMedGoogle Scholar
  88. MILEDI, R. & SLATER, C. R. (1969) Electron-microscopic structure of denervated skeletal muscle. Proceedings of the Royal Society of London, B Biological Sciences 174, 25–269.Google Scholar
  89. MILEDI, R. & SLATER, C. R. (1970) On the degeneration of rat neuromuscular junctions after nerve section. Journal of Physiology 207, 50–528.PubMedGoogle Scholar
  90. MIURA, H., ODA, K., ENDO, C., YAMAZAKI, K., SHIBASAKI, H. & KIKUCHI, T. (1993) Progressive degeneration of motor nerve terminals in gad mutant mouse with hereditary sensory axonopathy. Neuropathology and Applied Neurobiology 19, 4–51.PubMedGoogle Scholar
  91. MIZUNO, Y., HATTORI, N., MORI, H., SUZUKI, T. & TANAKA, K. (2001) Parkin and parkinson's disease. Current Opinion in Neurology 14, 47–482.PubMedGoogle Scholar
  92. MURPHEY, R. K. & GODENSCHWEGE, T. A. (2002) New roles for ubiquitin in the assembly and function of neuronal circuits. Neuron 26, –8.Google Scholar
  93. NGUYEN, Q. T., PARSADANIAN, A. S., SNIDER, W. D. & LICHTMAN, J. W. (1998) Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science 279, 172–1729.PubMedGoogle Scholar
  94. O'BRIEN, R. A., OSTBERG, A. J. & VRBOVA, G. (1978) Persistent polyneuronal innervation in hyperinnervated skeletal muscle. Journal of Physiology 280, 38P.Google Scholar
  95. O'BRIEN, R. A., OSTBERG, A. J. & 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, 63–646.PubMedGoogle Scholar
  96. O'HANLON, G. M., PLOMP, J. J., CHAKRABARTI, M., MORRISON, I., WAGNER, E. R., GOODYEAR, C. S., YIN, X., TRAPP, B. D. T., CONNER, J., MOLENAAR, P. C., STEWART, S., ROWAN, E. G. & WILLISON, H. J. (2001) Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal. Brain 124, 89–906.PubMedGoogle Scholar
  97. OH, C. E., MCMAHON, R., BENZER, S. & TANOUYE, M. A. (1994) Bendless, a drosophila gene affecting neuronal connectivity, encodes a ubiquitin-conjugating enzyme homolog. Journal of Neuroscience 14, 16– 179.Google Scholar
  98. ORIAN, A., GONEN, H., BERCOVICH, B., FAJERMAN, I., EYTAN, E., ISRAEL, A., MERCURIO, F., IWAI, K., SCHWARTZ, A. L. & Ciechanover, A. (2000) SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its Cterminus by IkappaB kinase. EMBO 19, 258–2591.Google Scholar
  99. PARSON, S. H., MACKINTOSH, C. L. & RIBCHESTER, R. R. (1997) Elimination of motor nerve terminals in neonatal mice expressing a gene for slow wallerian degeneration (C57Bl/Wlds). European Journal of Neuroscience 9, 158–1592.PubMedGoogle Scholar
  100. PERRY, V. H., BROWN, M. C. & LUNN, E. R. (1991) Very slow retrograde and wallerian degeneration in the CNS of C57Bl/Ola mice. European Journal of Neuroscience 3, 10–105.PubMedGoogle Scholar
  101. PESTRONK, A., CORNBLATH, D. R., ILYAS, A. A., BABA, H., QUARLES, R. H. & GRIFFIN, J. W. (1988) Atreatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Annals of Neurology 24, 7–78.PubMedGoogle Scholar
  102. PICKART, C. M. (1998) Polyubiquitin chains. In Ubiquitin and the Biology of the Cell (edited by PETERS, J.-M., HARRIS, J. R. & FINLEY, D.) pp. 1–63. New York: Plenum Press.Google Scholar
  103. PLOMP, J. J., MOLENAAR, P. C., O'HANLON, G. M., JACOBS, B. C., VEITCH, J., DAHA, M. R., VAN DOORN, P. A., VAN DER MECHE, F. G., VINCENT, A., MORGAN, B. P. & WILLISON, H. J. (1999) Miller Fisher anti GQ1b antibodies: Alpha-latrotoxin-like effects on motor end plates. Annals of Neurology 45, 18–199.PubMedGoogle Scholar
  104. PUN, S., SIGRIST, M., SANTOS, A. F., RUEGG, M. A., SANES, J. R., JESSELL, T. M., ARBER, S. & CARONI, P. (2002) An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles. Neuron 34, 35–370.PubMedGoogle Scholar
  105. PURVES, D. (1988) Body and Brain: A Trophic Theory of Neural Connections. Cambridge, Mass: Harvard University Press.Google Scholar
  106. RAFF, M. C., WHITMORE, A. V. & FINN, J. T. (2002) Axonal destruction and neurodegeneration. Science 296, 86–871.PubMedGoogle Scholar
  107. RANVIER, L. (1889) Traité Technique D'Histologie, 2nd edn. Paris. Libraire F. Savy, pp. 61–637.Google Scholar
  108. REDFERN, P. A. (1970) Neuromuscular transmission in new-born rats. Journal of Physiology 209, 70–709.PubMedGoogle Scholar
  109. RIBCHESTER, R. R. (1988) Activity-dependent and-independent synaptic interactions during reinnervation of partially denervated rat muscle. Journal of Physiology 401, 5–75.PubMedGoogle Scholar
  110. RIBCHESTER, R. R. (2001) Development and plasticity of neuromuscular connections. In Brain and Behaviour in Human Neural Development (edited by KALVERBOER, A. F. & GRAMSBERGEN, A.) pp. 26–341. Kluwer Academic Press.Google Scholar
  111. RIBCHESTER, R. R. & TAXT, T. (1983) Motor unit size and synaptic competition in rat lumbrical muscles reinnervated by active and inactive motor axons. Journal of Physiology 344, 8–111.PubMedGoogle Scholar
  112. RIBCHESTER, R. R., THOMSON, D., HADDOW, L. J. & USHKARYOV, Y. A. (1998) Enhancement of spontaneous transmitter release at neonatal mouse neuromuscular junctions by the glial cell line-derived neurotrophic factor (GDNF). Journal of Physiology 512, 63–641.PubMedGoogle Scholar
  113. RIBCHESTER, R. R., TSAO, J. W., BARRY, J. A., ASGARI JIRANDEH, N., PERRY, V. H. & BROWN, M. C. (1995) Persistence of neuromuscular junctions after axotomy in mice with slow Wallerian degeneration (C57Bl/WldS). European Journal of Neuroscience 7, 164–1650.PubMedGoogle Scholar
  114. RICH, M. M. & LICHTMAN, J. W. (1989) Motor nerve terminal loss from degenerating muscle fibres. Neuron 3, 67–688.PubMedGoogle Scholar
  115. RICH, M. M., COLMAN, H. & LICHTMAN, J. W. (1994) In vivo imaging shows loss of synaptic sites from neuromuscular junctions in a model of myasthenia gravis. Neurology 44, 213–2144.PubMedGoogle Scholar
  116. RICH, M. M., WALDECK, R. F., CORK, L. C., BALICEGORDON, R. J., FYFFE, R. E. W., WANG, X., COPE, T. C. & PINTER, M. J. (2002) Reduced endplate currents underlie motor unit dysfunction in canine motor neuron disease. Journal of Neurophysiology 88, 329–3304.PubMedGoogle Scholar
  117. RICHMAN, D. P., GOMEZ, C. M., BERMAN, P. W., BURRES, S. A., FITCH, F. W. & ARNASON, B. G. W. (1980) Monoclonal anti-acetylcholine receptor antibodies can cause experimental myasthenia. Nature 286, 73–739.PubMedGoogle Scholar
  118. RIDGE, R. M. & BETZ, W. J. (1984) The effect of selective, chronic stimulation on motor unit size in developing rat muscle. Journal of Neuroscience 4, 261–2620.PubMedGoogle Scholar
  119. RILEY, D. A. (1977) Spontaneous elimination of nerve terminals fromthe endplates of developing skeletal myofibers. Brain Research 134, 27–285.PubMedGoogle Scholar
  120. RILEY, D. A. (1981) Ultrastructural evidence for axon retraction during the spontaneous elimination of polyneuronal innervation of the rat soleus muscle. Journal of Neurocytology 10, 42–440.PubMedGoogle Scholar
  121. RIZO, J. & SUDHOF, T. C. (2002) Snares and Munc18 in synaptic vesicle fusion. Nature Reviews Neuroscience 3, 64–653.PubMedGoogle Scholar
  122. ROSENTHAL, J. L. & TARASKEVICH, P. S. (1977) Reduction of multiaxonal innervation at the neuromuscular junction of the rat during development. Journal of Physiology 270, 29–310.PubMedGoogle Scholar
  123. SAIGOH, K., WANG, Y.-L., SUH, J.-G., YAMANISHI, T., SAKAI, Y., KIYOSAWA, H., HARADA, T., ICHIHARA, N., WAKANA, S., KIKUCHI, T. & WADA, K. (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nature Genetics 23, 4–51.PubMedGoogle Scholar
  124. SCHAEFER, A. M., HADWIGER, G. D. & NONET, M. L. (2000) Rpm-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans. Neuron 26, 34–356.PubMedGoogle Scholar
  125. SCHAEFER, A. M., SANES, J. R. & LICHTMAN, J. W. (2002) Synapses and motor units in mouse models of ALS and SMA. Program No. 535.4. 2002 Abstract Viewer, Washington, DC; Society for Neuroscience, 2002. CDROM.Google Scholar
  126. SCHOSER, B. G. & BLOTTNER, D. (1999) Matrix metalloproteinases MMP-2, MMP-7 and MMP-9 in denervated human muscle. Neuroreport 19, 279– 2797.Google Scholar
  127. SELKOE, D. J. (2002) Alzheimer's disease is a synaptic failure. Science 298, 78–791.PubMedGoogle Scholar
  128. SELKOE, D. J. & KOPAN, R. (2003) Notch and presenilin: Regulated intramembrane proteolysis links development and degeneration. Annual Review of Neuroscience 26, 56–597.PubMedGoogle Scholar
  129. SHERMAN, M. Y. & GOLDBERG, A. L. (2001) Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron 29, 1– 32.PubMedGoogle Scholar
  130. SHI, B. & STANFIELD, B. B. (1996) Differential sprouting responses in axonal fiber systems in the dentate gyrus following lesions of the perforant path in WldS mutant mice. Brain Research 740, 8–101.PubMedGoogle Scholar
  131. SINGH, B. R. (2000) Intimate details of the most poisonous poison. Nature Structural Biology 7, 61–619.PubMedGoogle Scholar
  132. SISODIA, S. S. (1999) Alzheimer's disease: Perspectives for the new millennium. Journal of Clinical Investigation 104, 116–1170.PubMedGoogle Scholar
  133. SLATER, C. (2001) Double agents and breakdown of integrity at the neuromuscular junction in Miller-Fisher syndrome. Brain 124, 84–848.PubMedGoogle Scholar
  134. SPENCER, P. S. & SCHAUMBURG, H. H. (1976) Centralperipheral distal axonopathy. The pathology of dyingback polyneuropathies. Progress in Neuropathology 3, 25–295.Google Scholar
  135. SWAMINATHAN, S. & ESWARAMOORTHY, S. (2000) Structural analysis of the catalytic and binding sites of clostridium botulinum neurotoxin B. Nature Structural Biology 7, 61–619.PubMedGoogle Scholar
  136. TAXT, T. (1983) Local and systemic effects of tetrodotoxin on the formation and elimination of synapses in reinnervated adult rat muscle. Journal of Physiology 340, 17– 194.PubMedGoogle Scholar
  137. TELLO, J. F. (1907)Dégéneration et régéneration des plaques motrices aprés la section des nerfs. Trav. Lab Recherches Biol 5, 11–149.Google Scholar
  138. TELLO, J. F. (1917) Genesis de las terminaciones nerviosas motrices y sensitivas. Trab. Lab. Invest. Biol. Univ. Madr. 15, 10–199.Google Scholar
  139. THOMAS, J. B. & WYMAN, R. J. (1984) Mutations altering synaptic connectivity between identified neurons in Drosophila. Journal of Neuroscience 4, 53–538.PubMedGoogle Scholar
  140. THOMPSON, W. (1983) Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use. Nature 302, 61–616.PubMedGoogle Scholar
  141. THOMPSON, W., KUFFLER, D. P. & JANSEN, J. K. (1979) The effect of prolonged, reversible block of nerve impulses on the elimination of polyneuronal innervation of new-born rat skeletal muscle fibers. Neuroscience 4, 27–281.PubMedGoogle Scholar
  142. URUSHITANI, M., KURISU, J., TSUKITA, K. & TAKAHASHI, R. (2002) Proteosomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. Journal of Neurochemistry 83, 103–1042.PubMedGoogle Scholar
  143. USHKARYOV, Y. (2002) Alpha-latrotoxin: From structure to some functions. Toxicon 40, –5.PubMedGoogle Scholar
  144. VAN DER PUTTEN, H., WIEDERHOLD, K.-H., PROBST, A., BARBIERI, S., MISTL, C., DANNER, S., KAUFFMANN, S., HOFELE, K., SPOOREN, W. P. J. M., RUEGG, M. A., LIN, S., CARONI, P., SOMMER, B., TOLNAY, M. & BILBE, G. (2000) Neuropathology in mice expressing human ?-synuclein. Journal of Neuroscience 20, 602–6029.PubMedGoogle Scholar
  145. VAN LEEUWEN, F. W., DE KLEIJN, D. P. V., VAN DEN HURK, H. H., NEUBAUER, A., SONNEMANS, M. A. F., SLUIJS, J. A., KOYCU, S., RAMDJIELAL, R. D. J., SALEHI, A., MARTENS, G. J. M., CROSVELD, F. G., BURBACH, P. H. & HOL, E. M. (1998) Frameshift mutants of beta amyloid precursor protein and ubiquitin-in alzheimer's and down patients. Science 279, 24–247.PubMedGoogle Scholar
  146. VAN OOYEN, A. & RIBCHESTER, R. R. (2003) Competition in the development of nerve connections. In Modelling Neural Development (edited by VAN OOYEN, A.) pp. 18–211. Cambridge, Massachusetts: MIT Press.Google Scholar
  147. WALLER, A. (1850) Experiments on the section of the glossopharyngeal and hyoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Philosophical Transactions of the Royal Society 140, 42– 429.Google Scholar
  148. WALSH, M. & LICHTMAN, J. W. (2003) In vivo timelapse imaging of synaptic takeover associated with naturally-occurring synapse elimination. Neuron 37, 6– 73.PubMedGoogle Scholar
  149. WAN, H. I., DIANTONIO, A., FETTER, R. D., BERGSTROM, K., STRAUSS, R. & GOODMAN, C. S. (2000) Highwire regulates synaptic growth in drosophila. Neuron 26, 31–329.PubMedGoogle Scholar
  150. WANG, M. S., FANG, G., CULVER, D. G., DAVIS, A. A., RICH, M. M. & GLASS, J. D. (2001) The WldS protein protects against axonal degeneration: A model of gene therapy for peripheral neuropathy. Annals of Neurology 50, 77–779.PubMedGoogle Scholar
  151. WATTS, R. J., HOOPFER, E. D. & LUO, L. (2003) Axon pruning during drosophila metamorphosis: Evidence for local degeneration and requirement of the ubiquitin-proteasome system. Neuron 38, 87– 885.PubMedGoogle Scholar
  152. WEISSMAN, A. M. (2001) Themes and variations on ubiquitylation. Nature Reviews Molecular Cell Biology 2, 16– 178.PubMedGoogle Scholar
  153. WILSON, S. M., BHATTACHARYYA, B., RACHEL, R. A., COPPOLA, V., TESSAROLLO, L., HOUSEHOLDER, D. B., FLETCHER, C. F., MILLER, R. J., COPELAND, N. G. & JENKINS, N. A. (2002) Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nature Genetics 32, 42– 425.PubMedGoogle Scholar
  154. WINLOW, W. & USHERWOOD, P. N. R. (1975) Ultrastructural studies of normal and degenerating mouse neuromuscular junctions. Journal of Neurocytology 4, 37– 394.PubMedGoogle Scholar
  155. ZHAI, Q., WANG, J., KIM, A., LIU, Q., WATTS, R. J., HOOPFER, E., MITCHISON, T., LUO, L. & HE, Z. (2003) Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration. Neuron 39, 21–225.PubMedGoogle Scholar
  156. ZHANG, Y., GAO, J., CHUNG, K. K. K., HUANG, H., DAWSON, V. L. & DAWSON, T. M. (2000) Degeneration of neuromuscular synapses 881 Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proceedings of the National Academy of Sciences, USA 97, 1335– 13359.Google Scholar
  157. ZHEN, M., HUANG, X., BAMBER, B. & JIN, Y. (2000) Regulation of presynaptic terminal organization by C. elegans rpm-1, a putative guanine nucleotide exchanger with a ring-h2 finger domain. Neuron 26, 33– 343.PubMedGoogle Scholar
  158. ZOUBINE, M. N., MA, J. Y., SMIRNOVA, I. V., CITRON, B. A. & FESTOFF, B. W. (1996) A molecular mechanism for synapse elimination: Novel inhibition of locally generated thrombin delays synapse loss in neonatal mouse muscle. Developmental Biology 179, 44– 457.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Thomas H. Gillingwater
    • 1
  • Richard R. Ribchester
    • 1
    Email author
  1. 1.Division of NeuroscienceUniversity of EdinburghEdinburghUK

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