Skip to main content
Log in

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

  • Published:
Journal of Neurocytology

Abstract

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 Wld S 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 Wld S 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 Wld S 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • AIRAKSINEN, M. S. & SAARMA, M. (2002) The GDNF family: Signalling, biological functions and therapeutic value. Nature Reviews Neuroscience 3, 38–394.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • BALICE-GORDON, R. J. & LICHTMAN, J. W. (1994) Long-term synapse loss induced by focal blockade of postsynaptic receptors. Nature 372, 51–524.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • BENOIT, P. & CHANGEUX, J. P. (1975) Consequences of tenotomy on the evolution of multiinnervation in developing rat soleus muscle. Brain Research 99, 35–358.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • BETZ, W. & SAKMANN, B. (1973) Effects of proteolytic enzymes on function and structure of frog neuromuscular junctions. Journal of Physiology 230, 67–688.

    PubMed  Google Scholar 

  • BIXBY, J. L. (1981) Ultrastructural observations on synapse elimination in neonatal rabbit skeletal muscle. Journal of Neurocytology 10, 8–100.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • CLINE, H. (2003) Synaptic plasticity: Importance of proteasome-mediated protein turnover. Current Biology 13, R51–R516.

    PubMed  Google Scholar 

  • COLEMAN, M. P. & PERRY, V. H. (2002) Axon pathology in neurological disease: A neglected therapeutic target. Trends in Neurosciences 25, 53–537.

    PubMed  Google Scholar 

  • COLMAN, H., NABEKURA, J. & LICHTMAN, J. W. (1997) Alterations in synaptic strength preceding axon withdrawal. Science 275, 35–361.

    PubMed  Google Scholar 

  • CONAWAY, R. C., BROWER, C. S. & CONAWAY, J. W. (2002) Emerging roles of ubiquitin in transcription regulation. Science 296, 125–1258.

    PubMed  Google Scholar 

  • 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 

  • CONNOLD, A. L. & VRBOVA, G. (1994) Neuromuscular contacts of expanded motor units in rat soleus muscles are rescued by leupeptin. Neuroscience 63, 32–338.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • COSTANZO, E. M., BARRY, J. A. & RIBCHESTER, R. R. (2000) Competition at silent synapses in reinnervated skeletal muscle. Nature Neuroscience 3, 69–700.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • EHLERS, M. D. (2003) Ubiquitin and synaptic dysfunction: Ataxic mice highlight new common themes in neurological disease. Trends in Neurosciences 26, –7.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • FISCHER, J. A. & OVERSTREET, E. (2002) Fat facets does a highwire act at the synapse. Bioessays 24, 1–16.

    PubMed  Google Scholar 

  • FLADBY, T. & JANSEN, J. K. (1987) Postnatal loss of synaptic terminals in the partially denervated mouse soleus muscle. Acta Physiologica Scandinavica 129, 23–246.

    PubMed  Google Scholar 

  • FRANK, E. (1997) Synapse elimination: for nerves it's all or nothing. Science 275, 32–325.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • GEORGE, J. M. (2001) The synucleins. Genome Biology 3, reviews 3002.–3002.6.

    Google Scholar 

  • GILLINGWATER, T. H. & RIBCHESTER, R. R. (2001) Compartmental neurodegeneration and synaptic plasticity in the WldS mutant mouse. Journal of Physiology 534, 62–639.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

  • GILLINGWATER, T. H., THOMSON, D. & RIBCHESTER, R. R. (2004) Myo-GDNF increases non-functional poly innervation of reinnervated mouse muscle. Neuroreport, In Press.

  • GLICKMAN, M. H. & CIECHANOVER, A. (2002) The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiological Reviews 82, 37–428.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • HEGDE, A. N. & DIANTONIO, A. (2002) Ubiquitin and the synapse. Nature Reviews Neuroscience 3, 85–861.

    PubMed  Google Scholar 

  • 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 

  • HICKE, L. (2001) Protein regulation by monoubiquitin. Nature Reviews Molecular Cell Biology 2, 19–201.

    PubMed  Google Scholar 

  • HOFFMAN, H. (1953) The persistence of hyperneurotized end-plates in mammalian muscles. Journal of Comparative Neurology 99, 33–345.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • IWAI, A. (2000) Properties of NACP/alpha-synuclein and its role in Alzheimer's disease. Biochim. Biophys. Acta. 26, 9–109.

    Google Scholar 

  • JENNINGS, C. (1994) Developmental neurobiology. Death of a synapse. Nature 372, 49–499.

    PubMed  Google Scholar 

  • JIRMANOVA, I. (1975) Ultrastructure of motor end-plates during pharmacologically-induced degeneration and subsequent regeneration of skeletal muscle. Journal of Neurocytology 4, 14–155.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • KASTHURI, N. & LICHTMAN, J. W. (2003) The role of neuronal identity in synaptic competition. Nature 424, 42–430.

    PubMed  Google Scholar 

  • KATZ, B. (1996) Neural transmitter release: From quantal secretion to exocytosis and beyond. The Fenn Lecture. Journal of Neurocytology 25, 67–686.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • KOTZBAUER, P. T., TROJANOWSK, J. Q. & LEE, V. M. (2001) Lewybody pathology in Alzheimer's disease. Journal of Molecular Neuroscience 17, 22–232.

    PubMed  Google Scholar 

  • 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 

  • KUIDA, K. (2000) Caspase-9. International Journal of Biochemistry and Cell Biology 32, 12–124.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • LAYFIELD, R., ALBAN, A., MAYER, R. J. & LOWE, J. (2001) The ubiquitin protein catabolic disorders. Neuropathology and Applied Neurobiology 27, 17–179.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • LOTHARIUS, J. & BRUNDIN, P. (2002) Pathogenesis of Parkinson's disease: Dopamine, vesicles and alphasynuclein. Nature Reviews Neuroscience 3, 93–942.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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 

  • MATTSON, M. P., PARTIN, J. & BEGLEY, J. G. (1998a) Amyloid ?-peptide induces apoptosis-related events in synapses and dendrites. Brain Research 807, 16– 176.

    PubMed  Google Scholar 

  • MATTSON, M. P., KELLER, J. N. & BEGLEY, J. G. (1998b) Evidence for synaptic apoptosis. Experimental Neurology 153, 3–48.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • MCARDLE, J. J. (1975) Complex end-plate potentials at the regenerating neuromuscular junction of the rat. Experimental Neurology 49, 62–638.

    PubMed  Google Scholar 

  • 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 

  • MILEDI, R. & SLATER, C. R. (1970) On the degeneration of rat neuromuscular junctions after nerve section. Journal of Physiology 207, 50–528.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • MIZUNO, Y., HATTORI, N., MORI, H., SUZUKI, T. & TANAKA, K. (2001) Parkin and parkinson's disease. Current Opinion in Neurology 14, 47–482.

    PubMed  Google Scholar 

  • MURPHEY, R. K. & GODENSCHWEGE, T. A. (2002) New roles for ubiquitin in the assembly and function of neuronal circuits. Neuron 26, –8.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • O'BRIEN, R. A., OSTBERG, A. J. & VRBOVA, G. (1978) Persistent polyneuronal innervation in hyperinnervated skeletal muscle. Journal of Physiology 280, 38P.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • PURVES, D. (1988) Body and Brain: A Trophic Theory of Neural Connections. Cambridge, Mass: Harvard University Press.

    Google Scholar 

  • RAFF, M. C., WHITMORE, A. V. & FINN, J. T. (2002) Axonal destruction and neurodegeneration. Science 296, 86–871.

    PubMed  Google Scholar 

  • RANVIER, L. (1889) Traité Technique D'Histologie, 2nd edn. Paris. Libraire F. Savy, pp. 61–637.

    Google Scholar 

  • REDFERN, P. A. (1970) Neuromuscular transmission in new-born rats. Journal of Physiology 209, 70–709.

    PubMed  Google Scholar 

  • RIBCHESTER, R. R. (1988) Activity-dependent and-independent synaptic interactions during reinnervation of partially denervated rat muscle. Journal of Physiology 401, 5–75.

    PubMed  Google Scholar 

  • 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.

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • RICH, M. M. & LICHTMAN, J. W. (1989) Motor nerve terminal loss from degenerating muscle fibres. Neuron 3, 67–688.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • RILEY, D. A. (1977) Spontaneous elimination of nerve terminals fromthe endplates of developing skeletal myofibers. Brain Research 134, 27–285.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • RIZO, J. & SUDHOF, T. C. (2002) Snares and Munc18 in synaptic vesicle fusion. Nature Reviews Neuroscience 3, 64–653.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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 

  • SELKOE, D. J. (2002) Alzheimer's disease is a synaptic failure. Science 298, 78–791.

    PubMed  Google Scholar 

  • SELKOE, D. J. & KOPAN, R. (2003) Notch and presenilin: Regulated intramembrane proteolysis links development and degeneration. Annual Review of Neuroscience 26, 56–597.

    PubMed  Google Scholar 

  • SHERMAN, M. Y. & GOLDBERG, A. L. (2001) Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron 29, 1– 32.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • SINGH, B. R. (2000) Intimate details of the most poisonous poison. Nature Structural Biology 7, 61–619.

    PubMed  Google Scholar 

  • SISODIA, S. S. (1999) Alzheimer's disease: Perspectives for the new millennium. Journal of Clinical Investigation 104, 116–1170.

    PubMed  Google Scholar 

  • SLATER, C. (2001) Double agents and breakdown of integrity at the neuromuscular junction in Miller-Fisher syndrome. Brain 124, 84–848.

    PubMed  Google Scholar 

  • SPENCER, P. S. & SCHAUMBURG, H. H. (1976) Centralperipheral distal axonopathy. The pathology of dyingback polyneuropathies. Progress in Neuropathology 3, 25–295.

    Google Scholar 

  • SWAMINATHAN, S. & ESWARAMOORTHY, S. (2000) Structural analysis of the catalytic and binding sites of clostridium botulinum neurotoxin B. Nature Structural Biology 7, 61–619.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • TELLO, J. F. (1907)Dégéneration et régéneration des plaques motrices aprés la section des nerfs. Trav. Lab Recherches Biol 5, 11–149.

    Google Scholar 

  • TELLO, J. F. (1917) Genesis de las terminaciones nerviosas motrices y sensitivas. Trab. Lab. Invest. Biol. Univ. Madr. 15, 10–199.

    Google Scholar 

  • THOMAS, J. B. & WYMAN, R. J. (1984) Mutations altering synaptic connectivity between identified neurons in Drosophila. Journal of Neuroscience 4, 53–538.

    PubMed  Google Scholar 

  • THOMPSON, W. (1983) Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use. Nature 302, 61–616.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • USHKARYOV, Y. (2002) Alpha-latrotoxin: From structure to some functions. Toxicon 40, –5.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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 

  • WALSH, M. & LICHTMAN, J. W. (2003) In vivo timelapse imaging of synaptic takeover associated with naturally-occurring synapse elimination. Neuron 37, 6– 73.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • WEISSMAN, A. M. (2001) Themes and variations on ubiquitylation. Nature Reviews Molecular Cell Biology 2, 16– 178.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • WINLOW, W. & USHERWOOD, P. N. R. (1975) Ultrastructural studies of normal and degenerating mouse neuromuscular junctions. Journal of Neurocytology 4, 37– 394.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard R. Ribchester.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gillingwater, T.H., Ribchester, R.R. The relationship of neuromuscular synapse elimination to synaptic degeneration and pathology: Insights from WldS and other mutant mice. J Neurocytol 32, 863–881 (2003). https://doi.org/10.1023/B:NEUR.0000020629.51673.f5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NEUR.0000020629.51673.f5

Keywords

Navigation